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Review

Polypeptide N-acetylgalactosaminyltransferase-Associated Phenotypes in Mammals

by
Kentaro Kato
1,2,*,
Lars Hansen
3,* and
Henrik Clausen
3
1
Department of Eco-Epidemiology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
2
School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
3
Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(18), 5504; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185504
Submission received: 23 July 2021 / Revised: 7 September 2021 / Accepted: 8 September 2021 / Published: 10 September 2021
(This article belongs to the Special Issue New Insights into Protein Glycosylation)
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Review Reports Versions Notes

Abstract

:
Mucin-type O-glycosylation involves the attachment of glycans to an initial O-linked N-acetylgalactosamine (GalNAc) on serine and threonine residues on proteins. This process in mammals is initiated and regulated by a large family of 20 UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) (EC 2.4.1.41). The enzymes are encoded by a large gene family (GALNTs). Two of these genes, GALNT2 and GALNT3, are known as monogenic autosomal recessive inherited disease genes with well characterized phenotypes, whereas a broad spectrum of phenotypes is associated with the remaining 18 genes. Until recently, the overlapping functionality of the 20 members of the enzyme family has hindered characterizing the specific biological roles of individual enzymes. However, recent evidence suggests that these enzymes do not have full functional redundancy and may serve specific purposes that are found in the different phenotypes described. Here, we summarize the current knowledge of GALNT and associated phenotypes.

1. Introduction

Initiation of mucin-type O-glycosylation is controlled by a large family of UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (EC 2.4.1.41; also referred to as GalNAc-Ts, ppGalNAc-Ts, and ppGaNTases) in animals. These enzymes catalyze formation of GalNAcα1-serine (Ser)/threonine (Thr) linkages in glycoproteins. In humans, 20 isoforms of GalNAc-Ts have been identified and several reviews have described these enzymes in detail [1,2,3]. The importance of each isoform is unclear because phenotypes lacking one or two isoforms have not been observed in experimental animals, except in Drosophila [4,5,6,7,8]. However, more recent studies have described GALNT mutation-related phenotypes in mammals. The purpose of this review is to summarize these phenotypes and to correct unintentional errors and nomenclature in the literature.

2. GALNT-Associated Phenotypes in Mammals

2.1. GALNT1-Related Phenotypes

The first molecular cloning and characterization were performed for GalNAc-T from bovine tissue [9,10]. Based on the bovine GALNT1 sequence, rat [11], porcine [12,13] and human [14,15] genes were identified. Murine Galnt1 is unpublished, but was directly submitted to GenBank by Hagen (GenBank: U73820.1). The amino acid sequence of murine GalNAc-T1 was published in 1997 [16]. GALNT1 and its protein are ubiquitously expressed in tissues and cell types at high levels [9,10,16,17,18]. This high and broad expression among tissues suggests that disruption of the gene would severely affect organisms. However, disruption of murine Galnt1 is not fatal and does not cause infertility, although Galnt1 deficiency does have moderate lethality and one-fourth of homozygous null mice, but not heterozygous mice, die in utero beyond E12.5 or before the age of one month for unknown reasons [19]. The moderate lethality observed in Galnt1 null mice might indicate that other GalNAc-Ts could partially compensate for GalNAc-T1.
In 2007, utilizing the Cre-loxP recombination system, Tenno et al. showed altered innate and adaptive immune cell trafficking in Galnt1-inactivated mice. This correlates with decreased expression of E- and P-selectin ligands on neutrophils and decreased expression of L-selectin ligands on lymph node high endothelial venules (HEVs). Increased apoptosis of B cells in the germinal center, resulting in impaired IgG production, also occurs in GalNAc-T1-deficient mice. A bleeding disorder was also observed in the mice, due to reduction of plasma levels of coagulation factors V, VII, VIII, IX, X and XII, even though platelet homeostasis was unaffected [20]. Immunological impairment of Galnt1-deficient mice has also been reported [21]. P-selectin-dependent and E-selectin-mediated leukocyte rolling were significantly impaired and L-selectin-dependent leukocyte rolling was completely abolished in Galnt1-deficient mice. P-selectin glycoprotein ligand-1 (PSGL-1) has been suggested to be a target protein for GalNAc-T1 O-glycosylation.
Loss of Galnt1 affects the early stages of murine organogenesis by disrupting secretion of components, especially laminin and collagen IV, of the basement membrane, which is a specialized extracellular matrix (ECM) that is important for mammalian development. Reduced cell proliferation and embryonic submandibular gland (SMG) growth, resulting in decreased integrin and FGF signaling, occur in Galnt1-deficient mice. Interestingly, induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), distinct from those observed in N-linked glycan deficiency, were observed in SMGs of these mice [22]. The same group also found impaired cardiac function in Galnt1-deficient adult mice. In this case, aberrant valve formation caused by increased cell proliferation of developing hearts resulted in aortic and pulmonary valve stenosis and regurgitation, left ventricular hypertrophy, cardiac dilation and valve thickening. In the developing valve tissues of Galnt1-deficient mice, transforming growth factor (TGF)-beta associated bone morphogenetic protein (BMP) signaling and mitogen-activated protein kinase (MAPK) signaling were increased. As an antagonist to BMP signaling, epidermal growth factor receptor (EGFR) signaling was decreased in these tissues. These alterations of signaling pathways resulted in increased cell proliferation and larger heart valves in the early stages of development. Expression of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteases, ADAMTS1 and ADAMTS5, which have important roles in valvulogenesis, was reduced at the protein level in developing valves of Galnt1-deficient mice, resulting in reduction of proteoglycan versican processing. For ECM proteins involved in cardiac development, reduced expression of cartilage link protein 1 (Crtl1) and increased accumulation of collagen I and fibronectin occurred in the mice. Unlike in embryonic SMGs of Galnt1-deficient mice, there was no ER stress in the developing heart tissue [19]. These observations are interesting, but the target proteins and underlying mechanisms in the GALNT1-related phenotypes are still unclear.

2.2. GALNT2-Related Phenotypes

The second GalNAc transferase, GalNAc-T2, was identified and purified from human placenta [15]. Based on the amino acid sequence, polymerase chain reaction (PCR) primers were generated and GALNT2 was obtained from a cDNA library of the gastric tumor cell line MKN45. Galnt2 and its protein are ubiquitously expressed in tissues and cell types at high levels in mice [18]. Recent genome-wide association studies (GWASs) have revealed associations of single nucleotide polymorphisms (SNPs) of GALNT2 with levels of plasma high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in humans [23,24,25,26]. Teslovich et al. further showed that liver-specific overexpression of Galnt2 using an adeno-associated virus (AAV) vector expression system reduced HDL-C levels, while shRNA-mediated knockdown of hepatic Galnt2 raised HDL-C in mice [26]. These results are supported by a study showing that a GalNAc-T2D314A (p.[Asp314Ala]) heterozygous mutation raised plasma HDL-C levels in humans. This may be due to a loss-of-function (LOF) in GalNAc-T2, caused by the mutation reducing O-glycosylation and activity of Apo-CIII, a protein that inhibits lipoprotein lipase (LPL), with a consequent increase in HDL-C [27].
In contrast, other GWAS and in vitro studies have shown that a modest increase in GALNT2 expression increases HDL-C levels [28]. Furthermore, two cases of human homozygous LOF mutations in hepatic GALNT2 with low levels of HDL-C and moderate reduction of TG in plasma were recently reported while searching for causes of heritable neurological traits and intellectual disability [29]. These mutations are a T>C in exon 3 of GALNT2 (p.[Phe104Ser]) and a nonsense mutation in exon 9 (p.[Gln289*]). Both are within a catalytic domain or between the catalytic domains of GalNAc-T2, leading to expression of a non-functional protein [29].
An explanation of the contrasting results among these studies was suggested by Khetarpal et al; overdose of AAV and AAV shRNA used in the earlier study caused GalNAc-T2-independent reduction and shRNA sequence-specific elevation in HDL-C levels, respectively [29]. For the mutated GalNAc-T2D314A enzyme, normal activity of the protein was confirmed [30] and a GalNAc-T2D314A homozygote had low HDL-C levels in humans, indicating that the higher HDL-C in heterozygotes in the earlier study was GALNT2-independent [29].
The major target proteins involved in these human phenotypes are angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C-III (ApoC-III) and phospholipid transfer protein (PLTP) [29,31,32]. GalNAc-T2 selectively glycosylates Thr226 of ANGPTL3 adjacent to the furin-like proprotein convertase processing site, and O-glycosylation of this site blocks protein cleavage in vitro. Cleavage of ANGPTL3 at this site leads to activation of the protein [33] as an inhibitor of LPL [34] and endothelial lipase (EL) [35]; therefore, LOF of GalNAc-T2 will increase ANGPTL3 activity, lower LPL activity and reduce HDL-C levels. This has been shown clearly in cultured cells and in mice [36]. GalNAc-T2 glycosylates Thr74 of ApoC-III, and if O-glycosylation stabilizes the protein, elevated Apo-CIII will lower LPL and increase plasma TG, although species-specific regulation of plasma TG levels has also been reported [29,36,37,38]. The effect of O-glycosylation on Thr74 of ApoC-III clearly requires further study, because the absence of O-glycosylation at Thr74 did not affect Apo-CIII secretion or binding affinity for lipoprotein in vitro [39], and resulted in normal TG, HDL and ApoC-III levels in humans [40].
Plasma PLTP activity is negatively associated with HDL-C levels and positively associated with TG levels [41]. PLTP activities are partially lowered in rodents and in humans, even though protein expression in plasma was not affected by GALNT2 deficiency [29]. This partial inhibition of activity can be explained by the ability of another major GalNAc-T expressed in liver—GalNAc-T1—to glycosylate the protein, although not as efficiently as GalNAc-T2 [29,31].
There are many players among lipases and in lipoprotein metabolism, and molecular regulation of lipoproteins is still not fully understood [42]. However, it is clear that GALNT2 deficiency lowers HDL-C levels and affects lipoprotein metabolism in rodents, nonhuman primates and humans. Novel congenital disorders with global development delay, intellectual disability and decreased HDL-C caused by GALNT2 deficiency in humans have recently been reported [43], and these multiple phenotypes also occur in Galnt2-deficient rodent models. This indicates that LOF of GalNAc-T2 affects the functions of protein substrates in different tissues. A summary of published GALNT2 mutations and associated phenotypes is shown in Table 1.

2.3. GALNT3-Related Phenotypes

Human GALNT3 was identified using the common sequences of GALNT1 and GALNT2 [44], and murine Galnt3 was identified from mouse testis [45]. In contrast to GALNT1 and GALNT2, expression of GALNT3 is highly regulated. Human GALNT3 is mainly found in the pancreas and testis, with lower expression in the kidney, prostate and intestine. Murine Galnt3 is highly expressed in the testis and moderately in other organs, including the sublingual gland, uterus, cervix, stomach, colon, kidney, submandibular gland and parotid gland [44,45].
Topaz et al. first reported GALNT3 mutation-associated hyperphosphatemic familial tumoral calcinosis (HFTC) cases in humans [46], and phenotype-related GALNT3 mutations have subsequently been reported in 62 cases from 39 families. Some of these cases were also summarized by Sun et al. [47] and Rafaelsen et al. [48]. Hyperostosis-hyperphosphatemia syndrome (HHS) is another clinical feature of GALNT3 deficiency; however, as concluded by Ichikawa et al. [49], we consider HFTC and HHS to be a continuous spectrum of the same disease and we describe both conditions as HFTC in this review. The mechanism underlying HFTC caused by GALNT3 mutation is a lack of O-glycosylation on Thr178 in a furin-like proprotein convertase processing site of phosphaturic factor FGF23; cleavage leads to inactivation of the factor [50].
The 62 reported HFTC cases in 39 families are summarized in Table 2. The disease is caused by both compound heterozygous and homozygous mutations of GALNT3. As shown in Table 2, there is no apparent difference in ethnicity, with 11 different ethnicities and a group of unknown ethnicities. A total of 36 different GALNT3 mutations are represented in the families, of which 16 are missense mutations, 6 are stop mutations, 9 are insertions or deletions causing a frameshift and 5 are splice site mutations (Table 3). The mutations are in all exons, except for exon 1 and exon 11. Exon 1 is a non-coding region of GALNT3 (NM_004482.4) and exon 11 contains the γ region of the lectin domain (Figure 1). In some previous studies, exon 1 has been skipped in numbering of exons and introns of GALNT3, but in this review, exon 1 is included in this numbering. The HFTC-related GALNT3 mutations are found in all domains, including the initiating ATG start codon, stem region, catalytic domain, linker region and lectin domain of the enzyme. Two of six cysteine residues involved in disulfide bridges in lectin domains of GalNAc-T3 are affected by missense mutations (p.[Cys561Ser] and p.[Cys574Gly]).
Other missense mutations in the catalytic and lectin domains of GalNAc-T3 are potential hypomorphic mutations. A missense mutation in the ATG start codon (p.[Met1Lys]) leads to complete loss of the entire GalNAc-T3 protein, while stop and frameshift mutations cause LOF of the catalytic or lectin domains. The lectin domain of GalNAc-T3 is required for O-glycosylation on Thr178 of FGF23 [51], in agreement with homozygous mutations in this domain (p.[Pro529Thrfs*17] and p.[Gln592*]) causing disease, even though the catalytic domains of GalNAc-T3 seem to be intact. Splice site mutations lead to exon skipping and cause LOF of the protein.
Galnt3-deficient or N-ethyl-N-nitrosourea (ENU)-induced GalNAc-T3W589R (p.[Trp589Arg])-mutated mice show moderate phenotypes of hyperphosphatemic tumoral carcinosis with decreased alkaline phosphatase activity and intact FGF23 levels [77,78]. Interestingly, Galnt3-deficient mice do not develop ectopic calcification, which is a phenotype in human HFTC, but GalNAc-T3W589R mice have this phenotype. Ichikawa et al. further showed that Galnt3-deficient male mice have growth retardation, infertility and increased bone mineral density, compared with wild-type mice [77]. These findings also occur in GalNAc-T3W589R mice [78], indicating that GalNAc-T3 activity is important for male infertility, consistent with the high GALNT3 expression in testis.
Mandel et al. showed strong expression of GalNAc-T3, but not GalNAc-T1, in human spermatozoa [79]. The same group also showed GalNAc-T3 expression in spermatocytes and spermatids, where T antigen (Gal-GalNAc-Ser/Thr) is expressed. Importantly, GalNAc-T3 was the only GalNAc-T isoform expressed in ejaculated spermatozoa (although GalNAc-T17 may also be present; see below) and had ring-shaped equatorial expression, indicating that this isoform has a specific role in germ cells [80]. The fraction of spermatozoa with equatorial expression of GalNAc-T3 was significantly lower in men with oligoteratoasthenozoospermia. Therefore, GalNAc-T3 expression seems to be related to the quality of spermatozoa, and GalNAc-T3 deficiency may lead to impaired O-glycosylation of proteins and abnormal maturation and function of spermatozoa [81]. One candidate protein is zonadhesin, a cell membrane adhesion molecule that plays a role in sperm–egg binding and has a mucin-like tandem repeat region that is heavily O-glycosylated [82,83]. Miyazaki et al. [84] showed that spermatozoa in Galnt3-deficient mice are rare and immotile, and have deformed round heads. A glycoprotein localized at the equatorial segment of the acrosome, equatorin, was identified as another candidate target protein specifically glycosylated by GalNAc-T3, possibly at Thr138. This site of O-glycosylation on equatorin is important for sperm–egg interaction in vitro and in vivo [85,86]. GALNT3 deficiency-related HFTC cases provided the first evidence for non-redundant functions of GalNAc-Ts in mammals. It is still unclear if HFTC males have reduced fertility, but O-glycosylation of sperm proteins by GalNAc-T3 seems to be important for sperm–egg interaction.

2.4. GALNT4-Related Phenotypes

Murine Galnt4 [16] is highly expressed in the sublingual gland, stomach and colon, and moderately expressed in the lung, small intestine, cervix and uterus. Human GALNT4 [87] is highly expressed in the liver, small intestine, stomach, pancreas, thyroid, spleen, lymph node and bone marrow. GalNAc-T4V506I (p.[Val506Ile]) carriers were shown to be associated with reduced risk of acute coronary syndrome (ACS), although the association was not significant in the haplotypic test [88].

2.5. GALNT5-Related Phenotypes

Rat Galnt5 is highly expressed in the sublingual gland and colon, and moderately in the stomach and small intestine [89]. The partial human GalNAc-T5 amino acid sequence was published in 1999 [90]. GALNT5-related phenotypes have not been reported in mammals so far.

2.6. GALNT6-Related Phenotypes

Human GALNT6 was identified as a close homolog of GALNT3 [83]. Human GALNT6 is expressed in the placenta and trachea, with weak signals in the brain and pancreas. Fibronectin is a good substrate for O-glycosylation by human GalNAc-T3 and GalNAc-T6, but not by GalNAc-T1 and GalNAc-T2, in vitro. However, GalNAc-T3 is not expressed in fibroblasts, in contrast to GalNAc-T6. These findings indicate that fibronectin is specifically glycosylated by GalNAc-T6 in vivo. Unlike GalNAc-T3, GalNAc-T6 is not expressed in human spermatozoa, whereas expression of GALNT6, but not GALNT3, occurs in the brain [83]. Related to this observation, Akasaka-Manya et al. showed that expression of several GALNTs, including GALNT6, is altered in sporadic Alzheimer’s disease progression in human brain. More prominent amyloid precursor protein (APP) O-glycosylation occurred through GalNAc-T6 compared to GalNAc-T1 or GalNAc-T4, and β-amyloid (Aβ1-40 and Aβ1-42) generation was reduced by overexpression of GalNAc-T6 without affecting the activities of secretases in vivo. This suggests that O-glycosylation of APP by GalNAc-T6 inhibits APP cleavage, and thereby decreases Aβ production [91]. Furthermore, downregulation of both GalNAc-T3 and GalNAc-T6 in the ectopic endometrium contributes to the development of endometriosis [92].

2.7. GALNT7-Related Phenotypes

Rat Galnt7 (first reported as Galnt6) was identified by Ten Hagen et al. and human GALNT7 was published by Bennet et al. in 1999 [90,93]. Rat and murine Galnt7 are expressed in the sublingual gland, stomach, small intestine and colon, with trace amounts in the ovary, cervix and uterus. Human GALNT7 is expressed ubiquitously, including in the stomach, thyroid, spinal cord, lymph node, trachea and adrenal gland, but not in bone marrow. This enzyme has a preference for GalNAc-glycosylated substrates and functions as a follow-up enzyme [90]. Genome-wide linkage analysis revealed that human GALNT7 is positively associated with schizophrenia, although the association was not statistically significant in quantitative PCR analyses [94]. A GWAS showed that neuritic plaques, a core neuropathologic feature of Alzheimer’s disease formed by β-amyloid deposits, are positively associated with GALNT7 [95]. Together with GalNAc-T6, GalNAc-T7 may control β-amyloid generation in Alzheimer’s disease.

2.8. GALNT8-Related Phenotypes

Human GALNT8 was cloned as an autosomal dominant hypophosphatemic rickets (ADHR) candidate gene from human fetal brain [96]. The tissue distribution of GALNT8 is high in the heart, skeletal muscle, kidney and liver; moderate in the placenta, small intestine, leukocyte and lung; and weak in the brain, colon, thymus and spleen. GALNT8 is highly polymorphic, but no substitutions are ADHR-related. The enzymatic activity of GalNAc-T8 was unclear until several studies showed that it might be a non-functional enzyme in vitro, despite weak expression of GALNT8 in the fetal brain, testis, colon and small intestine found by quantitative real-time PCR, in contrast to a previous study [97,98].

2.9. GALNT9-Related Phenotypes

Human GALNT9 shows brain-specific expression, especially in the cerebellum, frontal lobe, temporal lobe and putamen; weak expression in the cerebral cortex; and no expression in the medulla, occipital pole and spinal cord [99]. This distribution is consistent with quantitative real-time PCR results reported by Raman et al. [97]. Its enzymatic activity was shown by Zhang et al. [100] to be similar to GalNAc-T1 in terms of substrate specificities. GWAS in chickens showed that GALNT9 in the liver differed significantly between fat and lean broilers, and correlated with abdominal fat traits, but it is unclear if this is also true in mammals [101].

2.10. GALNT10-Related Phenotypes

Rat Galnt10 was identified (but referred to as Galnt9 at the time) by Ten Hagen et al., together with Galnt5 from rat sublingual gland [102]. The highest levels of rat Galnt10 occur in the sublingual gland, testis, small intestine, colon and ovary; with lower levels in the heart, brain, spleen, lung, stomach, cervix and uterus. GalNAc-T10 resembles GalNAc-T7, in that it also serves as a follow-up enzyme and does not utilize non-glycosylated peptides as substrates. Murine Galnt10 is predominantly expressed in several hypothalamic, thalamic and amygdalar nuclei in the brain. The broad expression of Galnt10 in mouse brain might indicate that the enzyme has a role in the central nervous system (CNS) [103]. Human GALNT10 was cloned as a homolog of human GALNT7. Quantitative real-time PCR revealed that human GALNT10 is ubiquitously expressed, with the highest levels in the small intestine, and intermediate levels in the stomach, pancreas, ovary, thyroid gland and spleen. Human GalNAc-T10 displays strong activity for glycosylated peptides, but negligible catalytic activity toward non-glycosylated peptides [104,105]. Interestingly, a further study showed that the catalytic domain of GalNAc-T10 is involved in site selection on glycopeptides, but the lectin domain is not required for catalysis [106]. Expression of Galnt10 in the brain in mice might be related to human schizophrenia, and a recent GWAS showed an unambiguous association between schizophrenia and GALNT10 with other glycosyltransferases [107]. Together with GalNAc-T7, follow-up or glycopeptide-preferring GalNAc-Ts may be associated with serious mental diseases, but further work is needed to draw a clear conclusion.

2.11. GALNT11-Related Phenotypes

Human and murine GALNT11 were identified in 2002 [5]. Human GALNT11 is highly expressed in the kidney and moderately expressed in the brain, heart and skeletal muscle; in contrast, murine Galnt11 is highly expressed only in the kidney. A recent GWAS identified an association between human GALNT11 and deterioration of kidney function [108], and an assessment of GalNAc-T11 function in the kidney by Tian et al. [109] showed that Galnt11-deficient mice suffered from low-molecular-weight proteinuria. The same study also identified the endocytic receptor megalin/LRP2, a member of the low-density lipoprotein receptor (LDLR) family, as a specific substrate for GalNAc-T11 in the kidney. Megalin showed reduced binding to endogenous ligands in the absence of Galnt11. Another important aspect of GALNT11 is that its expression is related to heterotaxy, a congenital heart disease resulting from abnormalities in left–right body patterning [110]. A case report of a 22-month-old male indicated that GALNT11, together with GALNT20 (GALNTL5), which seems to be a non-functional protein (see below), was associated with developmental delay, distinctive facial features and multiple congenital anomalies [111]. These observations may be related to Notch signaling activation due to Notch1 O-glycosylation by GalNAc-T11 [112]. Galnt11 and NOTCH1 knockdown and gain-of-function produced similar left–right patterning in Xenopus, suggesting that GALNT11 affects the Notch signaling pathway [112].

2.12. GALNT12-Related Phenotypes

Human GALNT12, which is most homologous to GALNT4, was cloned and shown to be expressed in digestive organs, including the stomach, small intestine, pancreas and colon. Moderate expression of GALNT12 occurs in the testis, thyroid gland and spleen [113]. Recent GWASs have shown that GALNT12 is negatively associated with serum galactose-deficient IgA1 levels resulting in IgA nephropathy [114], and a single nucleotide polymorphism (SNP)—rs2295926, belonging to GALNT12—is strongly associated with rapid radiographic joint destruction in patients with rheumatoid arthritis [115], but the underlying molecular mechanisms are unclear.

2.13. GALNT13-Related Phenotypes

Murine Galnt13 was cloned and published as a homolog of Galnt1 in 1995 [116]. T-cell specific depletion of the gene in mice resulted in no phenotype. Human GALNT13 was cloned and shown to be specifically expressed in the brain [100]. In this study, Galnt13 null mice were generated; they had a decrease in the Tn (GalNAc-Thr/Ser) antigen in Purkinje cell bodies and internal granular layer cells of the cerebellum cortex, compared with wild-type mice. However, the mice were fertile and developed normally. A case of a 13-year-old girl showed a relationship of GALNT13 with minor facial and digital anomalies, mild developmental delay during infancy and behavioral disorders, which might reflect high expression of GALNT13 in the brain [117].

2.14. GALNT14-Related Phenotypes

Human GALNT14 was cloned based on GALNT2 and is expressed specifically in the kidney [118]. Using autozygosity mapping and whole-exome sequencing, GALNT14 with homozygous mutation in exon13 (c.[1273C>T]) resulting in truncation of >75% of the protein sequence (p.[Arg425*]) has been linked to embryonic lethality [119]. A heterozygous intragenic deletion of 123 kb in GALNT14 was identified in an intestinal malrotation case by analysis of array comparative genomic hybridization (aCGH) data [120]. A whole-exome sequencing study revealed that a homozygous frameshift in GALNT14 (c.[60del] or p.[Leu21Cysfs*6]) was identified as the genetic cause of Keratoconus in two cases [121]. However, the molecular mechanisms behind these observations are yet to be known.

2.15. GALNT15 (GALNTL2)-Related Phenotypes

Human GALNT15 was cloned using cDNA of human cerebellum as a template. The transcripts were ubiquitously expressed in human tissues, with high expression in the placenta and small intestine, and moderate expression in the spleen, ovary and cerebral cortex [122]. Even though its enzymatic activity using peptide substrates was confirmed in vitro, GALNT15-related phenotypes in mammals have not been reported.

2.16. GALNT16 (GALNTL1)-Related Phenotypes

Human GALNT16 was directly submitted to GenBank (AB078143.1), and the expression and catalytic activity of human GalNAc-T16 were studied by Raman et al. [97]. The enzyme transfers GalNAc to a wide range of peptide substrates. Human GALNT16 has a broad distribution, with high expression in the heart and moderate expression in the brain and spinal cord. A recent GWAS reported an association with risk for cardiovascular disease [123]. In mice, Galnt16 expression was very low in the tissues tested, including brain, colon, heart, kidney, liver, lung, skeletal muscle, ovary, prostate, spleen, sublingual gland, testis, thymus and thyroid [18 (as GalNAc-Ta)], but upregulation through an unknown mechanism was observed in diabetic mice [124].

2.17. GALNT17 (GALNTL6)-Related Phenotypes

Human GALNT17 (described as GALNT20 at the time) was cloned based on the GALNT10 sequence, and showed high expression in the testis, brain and ovary [125]. In situ hybridization studies in mice indicated that Galnt17 might have functions in spermatogenesis. GalNAc-T17 is also a follow-up GalNAc-T and prefers glycosylated peptides as substrates [125]. These results were reconfirmed by Raman et al. [97]. Recent GWASs have revealed that GALNT17 (GALNTL6) polymorphism is associated with athletic performance through an unknown mechanism [126]. The data from the study suggested that GALNT17 (GALNTL6) rs558129 T allele carriers had significantly higher power values in a Wingate anaerobic test than those with the CC genotype. Furthermore, the T allele was overrepresented in power athletes compared with both endurance athletes and controls. Therefore, the GALNT17 (GALNTL6) rs558129 T allele could be favorable for anaerobic performance and strength of athletes [126]. A study in mice indicated that Galnt17 dysregulation is related to a phenotype in human Autism Susceptibility Candidate 2 (AUTS2) syndrome, although the underlying mechanism is unclear [127].

2.18. GALNT18 (GALNTL4)-Related Phenotypes

Human GalNAc-T18 is an interesting enzyme that is primarily distributed in the endoplasmic reticulum (ER), rather than in the Golgi apparatus, where other GalNAc-Ts are located [98,128,129]. Human GALNT18 is expressed ubiquitously, including in the lung, brain, uterus, placenta, testis and kidney [97,98], whereas mouse Galnt18 is expressed only in the lung [18 (as GalNAc-T8)]. Human GalNAc-T18 has highly specific substrate specificity and only two peptides (GTTAKPTTLKPTE and GAGAEAPTPAPAGAGK) have been identified that can be glycosylated by the enzyme [97,98]. A recent longitudinal and transancestral study showed a positive association between demethylation of a CpG site located within GALNT18 and development of active lupus nephritis [130]. In the study, a significant reduction in DNA methylation levels in a single CpG site (cg16204559) was observed during active nephritis in lupus patients. However, understanding the biological role of this demethylation in lupus nephritis will require further investigation [130].

2.19. GALNT19 (GALNTL3)-Related Phenotypes

Human and rat GALNT19 were cloned and published by Nakamura et al. as homologs of human GALNT9 [131]. As for GALNT9, human and rat GALNT19 are highly expressed in the brain, and human GALNT19 is also moderately expressed in the heart. Its enzymatic activities toward peptides are unclear [97, 98 (as GalNAc-T17), 131]. Interestingly, human GALNT19 was found to be identical to the gene WBSCR17, located in the critical region of patients with Williams–Beuren Syndrome, a neurodevelopmental disorder. Therefore, GalNAc-T19 may glycosylate brain-specific substrates in vivo [131].

2.20. GALNT20 (GALNTL5)-Related Phenotypes

Human GALNT20 is unique among GALNTs because it does not encode a lectin domain [97]. Highly specific expression of this gene in the testis has been detected in humans and mice [18,97]. Importantly, a heterozygous mutation of Galnt20 affected male fertility with impairment of sperm motility; however, enzyme activity of GalNAc-T20 against peptides could not be detected in vitro [97,132]. This might indicate that the panel of peptide substrates used for detecting GalNAc-T activity is not sufficient, and that there is a need to find “true substrates” and include these substrates in future assays.

3. Conclusions

Almost 10 years have passed since the 20th human GalNAc-T was cloned and published. Some of these enzymes seem to have roles in vivo, but their enzymatic activities have yet to be shown in vitro. Recent GWASs have revealed human phenotype-related GALNTs, and these studies may also be able to identify true substrates for each GalNAc-T in vivo. GalNAc-Ts may also have functions other than as GalNAc-transferases, which would be particularly interesting. Recently, the function of O-glycosylation of the proteins initiated by GalNAc-Ts has been reviewed in a broader perspective [133]. Most GALNTs are associated with carcinogenesis, as widely shown, but we have not included these findings in this review because the studies were reviewed by Hussain et al. recently [134]. Recent studies targeting each GALNT by microRNA (miRNA) were also not included, because a single miRNA targets several messenger RNAs and the publications reporting the studies are still few, although this would be an appropriate subject for a further review.

Author Contributions

Conceptualization, K.K., L.H. and H.C.; Writing—Original Draft Preparation, K.K. and L.H.; Writing—Review and Editing, K.K. and L.H.; Visualization, K.K. and L.H. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported in part by Danish National Research Foundation (DNRF107).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank Hideyuki Takeuchi (University of Shizuoka, School of Pharmaceutical Sciences) for giving us an opportunity to write this review for a Special Issue “New Insights into Protein Glycosylation” of the journal. We also thank Katrine Schjoldager (University of Copenhagen) for her helpful comments, especially on GALNT2.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Marth, J.D. Complexity in O-linked oligosaccharide biosynthesis engendered by multiple polypeptide N-acetylgalactosaminyltransferases. Glycobiology 1996, 6, 701–705. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Ten Hagen, K.G.; Fritz, T.A.; Tabak, L.A. All in the family: The UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases. Glycobiology 2003, 13, 1R–16R. [Google Scholar] [CrossRef] [Green Version]
  3. Bennett, E.P.; Mandel, U.; Clausen, H.; Gerken, T.A.; Fritz, T.A.; Tabak, L.A. Control of mucin-type O-glycosylation: A classification of the polypeptide GalNAc-transferase gene family. Glycobiology 2012, 22, 736–756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Flores, C.; Engels, W. Microsatellite instability in Drosophila spellchecker1 (MutS homolog) mutants. Proc. Natl. Acad. Sci. USA 1999, 96, 2964–2969. [Google Scholar] [CrossRef] [Green Version]
  5. Schwientek, T.; Bennett, E.P.; Flores, C.; Thacker, J.; Hollmann, M.; Reis, C.A.; Behrens, J.; Mandel, U.; Keck, B.; Schäfer, M.A.; et al. Functional conservation of subfamilies of putative UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferases in Drosophila, Caenorhabditis elegans, and mammals. One subfamily composed of l(2)35Aa is essential in Drosophila. J. Biol. Chem. 2002, 277, 22623–22638. [Google Scholar] [CrossRef] [Green Version]
  6. Ten Hagen, K.G.; Tran, D.T. A UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase is essential for viability in Drosophila melanogaster. J. Biol. Chem. 2002, 277, 22616–22622. [Google Scholar] [CrossRef] [Green Version]
  7. Ten Hagen, K.G.; Zhang, L.; Tian, E.; Zhang, Y. Glycobiology on the fly: Developmental and mechanistic insights from Drosophila. Glycobiology 2009, 19, 102–111. [Google Scholar] [CrossRef] [Green Version]
  8. Bennett, E.P.; Chen, Y.W.; Schwientek, T.; Mandel, U.; Schjoldager, K.T.; Cohen, S.M.; Clausen, H. Rescue of Drosophila melanogaster l(2)35Aa lethality is only mediated by polypeptide GalNAc-transferase pgant35A, but not by the evolutionary conserved human ortholog GalNAc-transferase-T11. Glycoconj. J. 2010, 27, 435–444. [Google Scholar] [CrossRef]
  9. Hagen, F.K.; Vanwuyckhuyse, B.; Tabak, L.A. Purification, Cloning, and Expression of a Bovine UDP-GalNAc: Polypeptide N-Acetyl-galactosaminyltransferae. J. Biol. Chem. 1993, 268, 18960–18965. [Google Scholar] [CrossRef]
  10. Homa, F.L.; Hollander, T.; Lehman, D.J.; Thomsen, D.R.; Elhammer, A.P. Isolation and expression of a cDNA clone encoding a bovine UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase. J. Biol. Chem. 1993, 268, 12609–12616. [Google Scholar] [CrossRef]
  11. Hagen, F.K.; Gregoire, C.A.; Tabak, L.A. Cloning and sequence homology of a rat UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase. Glycoconj. J. 1995, 12, 901–909. [Google Scholar] [CrossRef] [PubMed]
  12. Yoshida, A.; Hara, T.; Ikenaga, H.; Takeuchi, M. Cloning and expression of a porcine UDP-GalNAc: Polypeptide N-acetylgalactosaminyl transferase. Glycoconj. J. 1995, 12, 824–828. [Google Scholar] [CrossRef] [PubMed]
  13. Sangadala, S.; Swain, J.B.; McNear, A.; Mendicino, J. Cloning, expression and properties of porcine trachea UDP-galnac: Polypeptide N-acetylgalactosaminyl transferase. Mol. Cell. Biochem. 2004, 266, 117–126. [Google Scholar] [CrossRef]
  14. Meurer, J.A.; Naylor, J.M.; Baker, C.A.; Thomsen, D.R.; Homa, F.L.; Elhammer, A.P. cDNA cloning, expression, and chromosomal localization of a human UDP-GalNAc:polypeptide, N-acetylgalactosaminyltransferase. J. Biochem. 1995, 118, 568–574. [Google Scholar] [CrossRef] [PubMed]
  15. White, T.; Bennett, E.P.; Takio, K.; Sørensen, T.; Bonding, N.; Clausen, H. Purification and cDNA cloning of a human UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase. J. Biol. Chem. 1995, 270, 24156–24165. [Google Scholar] [CrossRef] [Green Version]
  16. Hagen, F.K.; Ten Hagen, K.G.; Beres, T.M.; Balys, M.M.; VanWuyckhuyse, B.C.; Tabak, L.A. cDNA cloning and expression of a novel UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase. J. Biol. Chem. 1997, 272, 13843–13848. [Google Scholar] [CrossRef] [Green Version]
  17. Kingsley, P.D.; Hagen, K.G.; Maltby, K.M.; Zara, J.; Tabak, L.A. Diverse spatial expression patterns of UDP-GalNAc:polypeptide N-acetylgalactosaminyl-transferase family member mRNAs during mouse development. Glycobiology 2000, 10, 1317–1323. [Google Scholar] [CrossRef] [Green Version]
  18. Young, W.W., Jr.; Holcomb, D.R.; Ten Hagen, K.G.; Tabak, L.A. Expression of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase isoforms in murine tissues determined by real-time PCR: A new view of a large family. Glycobiology 2003, 13, 549–557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Tian, E.; Stevens, S.R.; Guan, Y.; Springer, D.A.; Anderson, S.A.; Starost, M.F.; Patel, V.; Ten Hagen, K.G.; Tabak, L.A. Galnt1 is required for normal heart valve development and cardiac function. PLoS ONE 2015, 10, e0115861. [Google Scholar] [CrossRef]
  20. Tenno, M.; Ohtsubo, K.; Hagen, F.K.; Ditto, D.; Zarbock, A.; Schaerli, P.; von Andrian, U.H.; Ley, K.; Le, D.; Tabak, L.A.; et al. Initiation of protein O glycosylation by the polypeptide GalNAcT-1 in vascular biology and humoral immunity. Mol. Cell. Biol. 2007, 27, 8783–8796. [Google Scholar] [CrossRef] [Green Version]
  21. Block, H.; Ley, K.; Zarbock, A. Severe impairment of leukocyte recruitment in ppGalNAcT-1-deficient mice. J. Immunol. 2012, 188, 5674–5681. [Google Scholar] [CrossRef] [Green Version]
  22. Tian, E.; Hoffman, M.P.; Ten Hagen, K.G. O-glycosylation modulates integrin and FGF signalling by influencing the secretion of basement membrane components. Nat. Commun. 2012, 3, 869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Willer, C.J.; Sanna, S.; Jackson, A.U.; Scuteri, A.; Bonnycastle, L.L.; Clarke, R.; Heath, S.C.; Timpson, N.J.; Najjar, S.S.; Stringham, H.M.; et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 2008, 40, 161–169. [Google Scholar] [CrossRef] [Green Version]
  24. Kathiresan, S.; Melander, O.; Guiducci, C.; Surti, A.; Burtt, N.P.; Rieder, M.J.; Cooper, G.M.; Roos, C.; Voight, B.F.; Havulinna, A.S.; et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 2008, 40, 189–197. [Google Scholar] [CrossRef] [PubMed]
  25. Kathiresan, S.; Willer, C.J.; Peloso, G.M.; Demissie, S.; Musunuru, K.; Schadt, E.E.; Kaplan, L.; Bennett, D.; Li, Y.; Tanaka, T.; et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 2009, 41, 56–65. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Teslovich, T.M.; Musunuru, K.; Smith, A.V.; Edmondson, A.C.; Stylianou, I.M.; Koseki, M.; Pirruccello, J.P.; Ripatti, S.; Chasman, D.I.; Willer, C.J.; et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010, 466, 707–713. [Google Scholar] [CrossRef]
  27. Holleboom, A.G.; Karlsson, H.; Lin, R.-S.; Beres, T.M.; Sierts, J.A.; Herman, D.S.; Stroes, E.S.G.; Aerts, J.M.; Kastelein, J.J.P.; Motazacker, M.M.; et al. Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man. Cell Metab. 2011, 14, 811–818. [Google Scholar] [CrossRef] [Green Version]
  28. Roman, T.S.; Marvelle, A.F.; Fogarty, M.P.; Vadlamudi, S.; Gonzalez, A.J.; Buchkovich, M.L.; Huyghe, J.R.; Fuchsberger, C.; Jackson, A.U.; Wu, Y.; et al. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol. Am. J. Hum. Genet. 2015, 97, 801–815. [Google Scholar] [CrossRef] [Green Version]
  29. Khetarpal, S.A.; Schjoldager, K.T.; Christoffersen, C.; Raghavan, A.; Edmondson, A.C.; Reutter, H.M.; Ahmed, B.; Ouazzani, R.; Peloso, G.M.; Vitali, C.; et al. Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents. Cell Metab. 2016, 24, 234–245. [Google Scholar] [CrossRef] [Green Version]
  30. Hansen, L.; Lind-Thomsen, A.; Joshi, H.J.; Pedersen, N.B.; Have, C.T.; Kong, Y.; Wang, S.; Sparso, T.; Grarup, N.; Vester-Christensen, M.B.; et al. A glycogene mutation map for discovery of diseases of glycosylation. Glycobiology 2015, 25, 211–224. [Google Scholar] [CrossRef] [Green Version]
  31. Schjoldager, K.T.; Vester-Christensen, M.B.; Bennett, E.P.; Levery, S.B.; Schwientek, T.; Yin, W.; Blixt, O.; Clausen, H. O-glycosylation modulates proprotein convertase activation of angiopoietin-like protein 3: Possible role of polypeptide GalNAc-transferase-2 in regulation of concentrations of plasma lipids. J. Biol. Chem. 2010, 285, 36293–36303. [Google Scholar] [CrossRef] [Green Version]
  32. Schjoldager, K.T.; Vakhrushev, S.Y.; Kong, Y.; Steentoft, C.; Nudelman, A.S.; Pedersen, N.B.; Wandall, H.H.; Mandel, U.; Bennett, E.P.; Levery, S.B.; et al. Probing isoform-specific functions of polypeptide GalNAc-transferases using zinc finger nuclease glycoengineered SimpleCells. Proc. Natl. Acad. Sci. USA 2012, 109, 9893–9898. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Ono, M.; Shimizugawa, T.; Shimamura, M.; Yoshida, K.; Noji-Sakikawa, C.; Ando, Y.; Koishi, R.; Furukawa, H. Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo. J. Biol. Chem. 2003, 278, 41804–41809. [Google Scholar] [CrossRef] [Green Version]
  34. Shimizugawa, T.; Ono, M.; Shimamura, M.; Yoshida, K.; Ando, Y.; Koishi, R.; Ueda, K.; Inaba, T.; Minekura, H.; Kohama, T.; et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J. Biol. Chem. 2002, 277, 33742–33748. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Shimamura, M.; Matsuda, M.; Yasumo, H.; Okazaki, M.; Fujimoto, K.; Kono, K.; Shimizugawa, T.; Ando, Y.; Koishi, R.; Kohama, T.; et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 366–372. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Li, X.; Zhang, Y.; Zhang, M.; Wang, Y. GALNT2 regulates ANGPTL3 cleavage in cells and in vivo of mice. Sci. Rep. 2020, 10, 16168. [Google Scholar] [CrossRef]
  37. Jong, M.C.; Hofker, M.H.; Havekes, L.M. Role of ApoCs in lipoprotein metabolism: Functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 472–484. [Google Scholar] [CrossRef] [Green Version]
  38. Qamar, A.; Khetarpal, S.A.; Khera, A.V.; Qasim, A.; Rader, D.J.; Reilly, M.P. Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1880–1888. [Google Scholar] [CrossRef] [Green Version]
  39. Roghani, A.; Zannis, V.I. Mutagenesis of the glycosylation site of human ApoCIII. O-linked glycosylation is not required for ApoCIII secretion and lipid binding. J. Biol. Chem. 1988, 263, 17925–17932. [Google Scholar] [CrossRef]
  40. Maeda, H.; Uzawa, H.; Kamei, R. Unusual familial lipoprotein C-III associated with apolipoprotein C-III-O preponderance. Biochim. Biophys. Acta 1981, 665, 578–585. [Google Scholar] [CrossRef]
  41. Chen, X.; Sun, A.; Mansoor, A.; Zou, Y.; Ge, J.; Lazar, J.M.; Jiang, X.-C. Plasma PLTP activity is inversely associated with HDL-C levels. Nutr. Metab. 2009, 6, 49. [Google Scholar] [CrossRef] [Green Version]
  42. Jin, W.; Marchadier, D.; Rader, D.J. Lipases and HDL metabolism. Trends Endocrinol. Metab. 2002, 13, 174–178. [Google Scholar] [CrossRef]
  43. Zilmer, M.; Edmondson, A.C.; Khetarpal, S.A.; Alesi, V.; Zaki, M.S.; Rostasy, K.; Madsen, C.G.; Lepri, F.R.; Sinibaldi, L.; Cusmai, R.; et al. Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function. Brain 2020, 143, 1114–1126. [Google Scholar] [CrossRef] [PubMed]
  44. Bennett, E.P.; Hassan, H.; Clausen, H. cDNA cloning and expression of a novel human UDP-N-acetyl-alpha-D-galactosamine. Polypeptide N-acetylgalactosaminyltransferase, GalNAc-t3. J. Biol. Chem. 1996, 271, 17006–17012. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Zara, J.; Hagen, F.K.; Ten Hagen, K.G.; Van Wuyckhuyse, B.C.; Tabak, L.A. Cloning and expression of mouse UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase-T3. Biochem. Biophys. Res. Commun. 1996, 228, 38–44. [Google Scholar] [CrossRef]
  46. Topaz, O.; Shurman, D.L.; Bergman, R.; Indelman, M.; Ratajczak, P.; Mizrachi, M.; Khamaysi, Z.; Behar, D.; Petronius, D.; Friedman, V.; et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat. Genet. 2004, 36, 579–581. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Sun, L.; Zhao, L.; Du, L.; Zhang, P.; Zhang, M.; Li, M.; Liu, T.; Ye, L.; Tao, B.; Zhao, H.; et al. Identification of two novel mutations in the GALNT3 gene in a Chinese family with hyperphosphatemic familial tumoral calcinosis. Bone Res. 2016, 4, 16038. [Google Scholar] [CrossRef]
  48. Rafaelsen, S.; Johansson, S.; Ræder, H.; Bjerknes, R. Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature. BMC Genet. 2014, 15, 98. [Google Scholar] [CrossRef] [Green Version]
  49. Ichikawa, S.; Baujat, G.; Seyahi, A.; Garoufali, A.G.; Imel, E.A.; Padgett, L.R.; Austin, A.M.; Sorenson, A.H.; Pejin, Z.; Topouchian, V.; et al. Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations. Am. J. Med. Genet. Part A 2010, 152A, 896–903. [Google Scholar] [CrossRef] [Green Version]
  50. Kato, K.; Jeanneau, C.; Tarp, M.A.; Benet-Pagès, A.; Lorenz-Depiereux, B.; Bennett, E.P.; Mandel, U.; Strom, T.M.; Clausen, H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J. Biol. Chem. 2006, 281, 18370–18377. [Google Scholar] [CrossRef] [Green Version]
  51. de Las Rivas, M.; Daniel, E.J.P.; Narimatsu, Y.; Compañón, I.; Kato, K.; Hermosilla, P.; Thureau, A.; Ceballos-Laita, L.; Coelho, H.; Bernadó, P.; et al. Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3. Nat. Chem. Biol. 2020, 16, 351–360. [Google Scholar] [CrossRef]
  52. Gok, F.; Chefetz, I.; Indelman, M.; Kocaoglu, M.; Sprecher, E. Newly discovered mutations in the GALNT3 gene causing autosomal recessive hyperostosis-hyperphosphatemia syndrome. Acta Orthop. 2009, 80, 131–134. [Google Scholar] [CrossRef] [Green Version]
  53. Mahjoubi, F.; Ghadir, M.; Samanian, S.; Heydari, I.; Honardoost, M. Hyperphosphatemic familial tumoral calcinosis caused by a novel variant in the GALNT3 gene. J. Endocrinol. Investig. 2020, 43, 1125–1130. [Google Scholar] [CrossRef]
  54. Ichikawa, S.; Imel, E.A.; Sorenson, A.H.; Severe, R.; Knudson, P.; Harris, G.J.; Shaker, J.L.; Econs, M.J. Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene. J. Clin. Endocrinol. Metab. 2006, 91, 4472–4475. [Google Scholar] [CrossRef] [Green Version]
  55. Joseph, L.; Hing, S.N.; Presneau, N.; O’Donnell, P.; Diss, T.; Idowu, B.D.; Joseph, S.; Flanagan, A.M.; Delaney, D. Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: Novel missense mutations in GALNT3. Skeletal. Radiol. 2010, 39, 63–68. [Google Scholar] [CrossRef]
  56. Yancovitch, A.; Hershkovitz, D.; Indelman, M.; Galloway, P.; Whiteford, M.; Sprecher, E.; Kılıç, E. Novel mutations in GALNT3 causing hyperphosphatemic familial tumoral calcinosis. J. Bone Miner. Metab. 2011, 29, 621–625. [Google Scholar] [CrossRef]
  57. Dumitrescu, C.E.; Kelly, M.H.; Khosravi, A.; Hart, T.C.; Brahim, J.; White, K.E.; Farrow, E.G.; Nathan, M.H.; Murphey, M.D.; Collins, M.T. A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features. Osteoporos. Int. 2009, 20, 1273–1278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Ramnitz, M.S.; Gourh, P.; Goldbach-Mansky, R.; Wodajo, F.; Ichikawa, S.; Econs, M.J.; White, K.E.; Molinolo, A.; Chen, M.Y.; Heller, T.; et al. Phenotypic and Genotypic Characterization and Treatment of a Cohort with Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome. J. Bone Miner. Res. 2016, 31, 1845–1854. [Google Scholar] [CrossRef] [Green Version]
  59. Olauson, H.; Krajisnik, T.; Larsson, C.; Lindberg, B.; Larsson, T.E. A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome. Eur. J. Endocrinol. 2008, 158, 929–934. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Finer, G.; Price, H.E.; Shore, R.M.; White, K.E.; Langman, C.B. Hyperphosphatemic familial tumoral calcinosis: Response to acetazolamide and postulated mechanisms. Am. J. Med. Genet. Part A 2014, 164, 1545–1549. [Google Scholar] [CrossRef] [PubMed]
  61. Dayal, D.; Gupta, S.; Kumar, R.; Srinivasan, R.; Lorenz-Depiereux, B.; Strom, T.M. A novel homozygous variant in exon 10 of the GALNT3 gene causing hyperphosphatemic familial tumoral calcinosis in a family from North India. Intractable Rare Dis. Res. 2021, 10, 55–57. [Google Scholar] [CrossRef] [PubMed]
  62. El Demellawy, D.; Chang, N.; de Nanassy, J.; Nasr, A. GALNT3 gene mutation-associated chronic recurrent multifocal osteomyelitis and familial hyperphosphatemic familial tumoral calcinosis. Scand. J. Rheumatol. 2015, 44, 170–172. [Google Scholar] [CrossRef]
  63. Vieira, A.R.; Lee, M.; Vairo, F.; Leite, J.C.L.; Munerato, M.C.; Visioli, F.; D’Ávila, S.R.; Wang, S.-K.; Choi, M.; Simmer, J.P.; et al. Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC). Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. 2015, 120, e235–e239. [Google Scholar] [CrossRef] [Green Version]
  64. Barbieri, A.M.; Filopanti, M.; Bua, G.; Beck-Peccoz, P. Two novel nonsense mutations in GALNT3 gene are responsible for familial tumoral calcinosis. J. Hum. Genet. 2007, 52, 464–468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Campagnoli, M.F.; Pucci, A.; Garelli, E.; Carando, A.; Defilippi, C.; Lala, R.; Ingrosso, G.; Dianzani, I.; Forni, M.; Ramenghi, U. Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a white family. J. Clin. Pathol. 2006, 59, 440–442. [Google Scholar] [CrossRef] [Green Version]
  66. Garringer, H.J.; Mortazavi, S.M.J.; Esteghamat, F.; Malekpour, M.; Boztepe, H.; Tanakol, R.; Davis, S.I.; White, K.E. Two novel GALNT3 mutations in familial tumoral calcinosis. Am. J. Med. Genet. Part A 2007, 143, 2390–2396. [Google Scholar] [CrossRef] [PubMed]
  67. Specktor, P.; Cooper, J.G.; Indelman, M.; Sprecher, E. Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred. J. Hum. Genet. 2006, 51, 487–490. [Google Scholar] [CrossRef] [Green Version]
  68. Garringer, H.J.; Fisher, C.; Larsson, T.E.; Davis, S.I.; Koller, D.L.; Cullen, M.J.; Draman, M.S.; Jain, N.C.A.; Fedarko, N.S.; Dasgupta, B.; et al. The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis. J. Clin. Endocrinol. Metab. 2006, 91, 4037–4042. [Google Scholar] [CrossRef]
  69. Ekinci, R.M.K.; Gürbüz, F.; Balcı, S.; Bişgin, A.; Taştan, M.; Yüksel, B.; Yılmaz, M. Hyperphosphatemic Familial Tumoral Calcinosis in Two Siblings with a Novel Mutation in GALNT3 Gene: Experience from Southern Turkey. J. Clin. Res. Pediatr. Endocrinol. 2019, 11, 94–99. [Google Scholar] [CrossRef]
  70. Guerra, M.G.; Videira, T.; de Fonseca, D.; Vieira, R.; dos Santos, J.; Pinto, S. Hyperphosphataemic familial tumoral calcinosis: Case report of a rare and challenging disease. Scand. J. Rheumatol. 2020, 49, 80–81. [Google Scholar] [CrossRef]
  71. Ichikawa, S.; Lyles, K.W.; Econs, M.J. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: Evidence that the disorder is autosomal recessive. J. Clin. Endocrinol. Metab. 2005, 90, 2420–2423. [Google Scholar] [CrossRef] [PubMed]
  72. Laleye, A.; Alao, M.J.; Gbessi, G.; Adjagba, M.; Marche, M.; Coupry, I.; Redonnet-Vernhet, I.; Lepreux, S.; Ayivi, B.; Darboux, R.B.; et al. Tumoral calcinosis due to GALNT3 C.516-2A >T mutation in a black African family. Genet. Couns. 2008, 19, 183–192. [Google Scholar]
  73. Masi, L.; Beltrami, G.; Ottanelli, S.; Franceschelli, F.; Gozzini, A.; Zonefrati, R.; Galli, G.; Ciuffi, S.; Mavilia, C.; Giusti, F.; et al. Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization. Calcif. Tissue Int. 2015, 96, 438–452. [Google Scholar] [CrossRef] [PubMed]
  74. Frishberg, Y.; Topaz, O.; Bergman, R.; Behar, D.; Fisher, D.; Gordon, D.; Richard, G.; Sprecher, E. Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders. J. Mol. Med. 2005, 83, 33–38. [Google Scholar] [CrossRef] [PubMed]
  75. Albaramki, J.; Dmour, H.; Shboul, M.; Bonnard, C.; Venkatesh, B.; Odeh, R. Recessive mutation in GALNT3 causes hyperphosphatemic familial tumoral calcinosis associated with chronic recurrent multifocal osteomyelitis. Turk. J. Pediatr. 2019, 61, 130–133. [Google Scholar] [CrossRef] [PubMed]
  76. Ichikawa, S.; Guigonis, V.; Imel, E.A.; Courouble, M.; Heissat, S.; Henley, J.D.; Sorenson, A.H.; Petit, B.; Lienhardt, A.; Econs, M.J. Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations. J. Clin. Endocrinol. Metab. 2007, 92, 1943–1947. [Google Scholar] [CrossRef]
  77. Ichikawa, S.; Sorenson, A.H.; Austin, A.M.; Mackenzie, D.S.; Fritz, T.A.; Moh, A.; Hui, S.L.; Econs, M.J. Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology 2009, 150, 2543–2550. [Google Scholar] [CrossRef] [Green Version]
  78. Esapa, C.T.; Head, R.A.; Jeyabalan, J.; Evans, H.; Hough, T.A.; Cheeseman, M.T.; McNally, E.G.; Carr, A.J.; Thomas, G.P.; Brown, M.A.; et al. A mouse with an N-Ethyl-N-nitrosourea (ENU) Induced Trp589Arg Galnt3 mutation represents a model for hyperphosphataemic familial tumoural calcinosis. PLoS ONE 2012, 7, e43205. [Google Scholar] [CrossRef] [Green Version]
  79. Mandel, U.; Hassan, H.; Therkildsen, M.H.; Rygaard, J.; Jakobsen, M.H.; Juhl, B.R.; Dabelsteen, E.; Clausen, H. Expression of polypeptide GalNAc-transferases in stratified epithelia and squamous cell carcinomas: Immunohistological evaluation using monoclonal antibodies to three members of the GalNAc-transferase family. Glycobiology 1999, 9, 43–52. [Google Scholar] [CrossRef] [Green Version]
  80. Rajpert-De Meyts, E.; Poll, S.N.; Goukasian, I.; Jeanneau, C.; Herlihy, A.S.; Bennett, E.P.; Skakkebaek, N.E.; Clausen, H.; Giwercman, A.; Mandel, U. Changes in the profile of simple mucin-type O-glycans and polypeptide GalNAc-transferases in human testis and testicular neoplasms are associated with germ cell maturation and tumour differentiation. Virchows Arch. 2007, 451, 805–814. [Google Scholar] [CrossRef]
  81. Nygaard, M.B.; Herlihy, A.S.; Jeanneau, C.; Nielsen, J.E.; Bennett, E.P.; Jørgensen, N.; Clausen, H.; Mandel, U.; Rajpert-De Meyts, E.; Almstrup, K. Expression of the O-Glycosylation Enzyme GalNAc-T3 in the Equatorial Segment Correlates with the Quality of Spermatozoa. Int. J. Mol. Sci. 2018, 19, 2949. [Google Scholar] [CrossRef] [Green Version]
  82. Hardy, D.M.; Garbers, D.L. A sperm membrane protein that binds in a species-specific manner to the egg extracellular matrix is homologous to von Willebrand factor. J. Biol. Chem. 1995, 270, 26025–26028. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Bennett, E.P.; Hassan, H.; Mandel, U.; Hollingsworth, M.A.; Akisawa, N.; Ikematsu, Y.; Merkx, G.; van Kessel, A.G.; Olofsson, S.; Clausen, H. Cloning and characterization of a close homologue of human UDP-N-acetyl-alpha-D-galactosamine:Polypeptide N-acetylgalactosaminyltransferase-T3, designated GalNAc-T6. Evidence for genetic but not functional redundancy. J. Biol. Chem. 1999, 274, 25362–25370. [Google Scholar] [CrossRef] [Green Version]
  84. Miyazaki, T.; Mori, M.; Yoshida, C.A.; Ito, C.; Yamatoya, K.; Moriishi, T.; Kawai, Y.; Komori, H.; Kawane, T.; Izumi, S.; et al. Galnt3 deficiency disrupts acrosome formation and leads to oligoasthenoteratozoospermia. Histochem. Cell Biol. 2013, 139, 339–354. [Google Scholar] [CrossRef] [PubMed]
  85. Toshimori, K.; Saxena, D.K.; Tanii, I.; Yoshinaga, K. An MN9 antigenic molecule, equatorin, is required for successful sperm-oocyte fusion in mice. Biol. Reprod. 1998, 59, 22–29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Yoshinaga, K.; Saxena, D.K.; Oh-oka, T.; Tanii, I.; Toshimori, K. Inhibition of mouse fertilization in vivo by intra-oviductal injection of an anti-equatorin monoclonal antibody. Reproduction 2001, 122, 649–655. [Google Scholar] [CrossRef]
  87. Bennett, E.P.; Hassan, H.; Mandel, U.; Mirgorodskaya, E.; Roepstorff, P.; Burchell, J.; Taylor-Papadimitriou, J.; Hollingsworth, M.A.; Merkx, G.; van Kessel, A.G.; et al. Cloning of a human UDP-N-acetyl-alpha-D-Galactosamine:polypeptide N-acetylgalactosaminyltransferase that complements other GalNAc-transferases in complete O-glycosylation of the MUC1 tandem repeat. J. Biol. Chem. 1998, 273, 30472–30481. [Google Scholar] [CrossRef] [Green Version]
  88. O’Halloran, A.M.; Patterson, C.C.; Horan, P.; Maree, A.; Curtin, R.; Stanton, A.; McKeown, P.P.; Shields, D.C. Genetic polymorphisms in platelet-related proteins and coronary artery disease: Investigation of candidate genes, including N-acetylgalactosaminyltransferase 4 (GALNT4) and sulphotransferase 1A1/2 (SULT1A1/2). J. Thromb. Thrombolysis 2009, 27, 175–184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Ten Hagen, K.G.; Hagen, F.K.; Balys, M.M.; Beres, T.M.; Van Wuyckhuyse, B.; Tabak, L.A. Cloning and expression of a novel, tissue specifically expressed member of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family. J. Biol. Chem. 1998, 273, 27749–27754. [Google Scholar] [CrossRef] [Green Version]
  90. Bennett, E.P.; Hassan, H.; Hollingsworth, M.A.; Clausen, H. A novel human UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase, GalNAc-T7, with specificity for partial GalNAc-glycosylated acceptor substrates. FEBS Lett. 1999, 460, 226–230. [Google Scholar] [CrossRef] [Green Version]
  91. Akasaka-Manya, K.; Kawamura, M.; Tsumoto, H.; Saito, Y.; Tachida, Y.; Kitazume, S.; Hatsuta, H.; Miura, Y.; Hisanaga, S.; Murayama, S.; et al. Excess APP O-glycosylation by GalNAc-T6 decreases Aβ production. J. Biochem. 2017, 161, 99–111. [Google Scholar] [CrossRef] [Green Version]
  92. Xu, X.; Fei, X.; Ma, J.; Qu, Y.; Zhou, C.; Xu, K.; Lin, J. Correlation of polypeptide N-acetylgalactosamine transferases-3 and -6 to different stages of endometriosis. Arch. Gynecol. Obstet. 2017, 295, 1413–1419. [Google Scholar] [CrossRef] [PubMed]
  93. Ten Hagen, K.G.; Tetaert, D.; Hagen, F.K.; Richet, C.; Beres, T.M.; Gagnon, J.; Balys, M.M.; VanWuyckhuyse, B.; Bedi, G.S.; Degand, P.; et al. Characterization of a UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase that displays glycopeptide N-acetylgalactosaminyltransferase activity. J. Biol. Chem. 1999, 274, 27867–27874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Vawter, M.P.; Atz, M.E.; Rollins, B.L.; Cooper-Casey, K.M.; Shao, L.; Byerley, W.F. Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia. Hum. Genet. 2006, 119, 558–570. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Beecham, G.W.; Hamilton, K.; Naj, A.C.; Martin, E.R.; Huentelman, M.; Myers, A.J.; Corneveaux, J.J.; Hardy, J.; Vonsattel, J.-P.; Younkin, S.G.; et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet. 2014, 10, e1004606. [Google Scholar] [CrossRef] [Green Version]
  96. White, K.E.; Lorenz, B.; Evans, W.E.; Meitinger, T.; Strom, T.M.; Econs, M.J. Molecular cloning of a novel human UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase, GalNAc-T8, and analysis as a candidate autosomal dominant hypophosphatemic rickets (ADHR) gene. Gene 2000, 246, 347–356. [Google Scholar] [CrossRef]
  97. Raman, J.; Guan, Y.; Perrine, C.L.; Gerken, T.A.; Tabak, L.A. UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferases: Completion of the family tree. Glycobiology 2012, 22, 768–777. [Google Scholar] [CrossRef] [Green Version]
  98. Li, X.; Wang, J.; Li, W.; Xu, Y.; Shao, D.; Xie, Y.; Xie, W.; Kubota, T.; Narimatsu, N.; Zhang, Y. Characterization of ppGalNAc-T18, a member of the vertebrate-specific Y subfamily of UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferases. Glycobiology 2012, 22, 602–615. [Google Scholar] [CrossRef] [Green Version]
  99. Toba, S.; Tenno, M.; Konishi, M.; Mikami, T.; Itoh, N.; Kurosaka, A. Brain-specific expression of a novel human UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T9). Biochim. Biophys. Acta 2000, 1493, 264–268. [Google Scholar] [CrossRef]
  100. Zhang, Y.; Iwasaki, H.; Wang, H.; Kudo, T.; Kalka, T.B.; Hennet, T.; Kubota, T.; Cheng, L.; Inaba, N.; Gotoh, M.; et al. Cloning and characterization of a new human UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase, designated pp-GalNAc-T13, that is specifically expressed in neurons and synthesizes GalNAc alpha-serine/threonine antigen. J. Biol. Chem. 2003, 278, 573–584. [Google Scholar] [CrossRef] [Green Version]
  101. Jin, P.; Wu, X.; Xu, S.; Zhang, H.; Li, Y.; Cao, Z.; Li, H.; Wang, S. Differential expression of six genes and correlation with fatness traits in a unique broiler population. Saudi J. Biol. Sci. 2017, 24, 945–949. [Google Scholar] [CrossRef] [Green Version]
  102. Ten Hagen, K.G.; Bedi, G.S.; Tetaert, D.; Kingsley, P.D.; Hagen, F.K.; Balys, M.M.; Beres, T.M.; Degand, P.; Tabak, L.A. Cloning and characterization of a ninth member of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family, ppGaNTase-T9. J. Biol. Chem. 2001, 276, 17395–17404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Nelson, P.A.; Sutcliffe, J.G.; Thomas, E.A. A new UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase mRNA exhibits predominant expression in the hypothalamus, thalamus and amygdala of mouse forebrain. Brain Res. Gene Expr. Patterns 2002, 1, 95–99. [Google Scholar] [CrossRef]
  104. Cheng, L.; Tachibana, K.; Zhang, Y.; Guo, J.M.; Tachibana, K.K.; Kameyama, A.; Wang, H.; Hiruma, T.; Iwasaki, H.; Togayachi, A.; et al. Characterization of a novel human UDP-GalNAc transferase, pp-GalNAc-T10. FEBS Lett. 2002, 531, 115–121. [Google Scholar] [CrossRef] [Green Version]
  105. Kubota, T.; Shiba, T.; Sugioka, S.; Furukawa, S.; Sawaki, H.; Kato, R.; Wakatsuki, S.; Narimatsu, H. Structural basis of carbohydrate transfer activity by human UDP-GalNAc: Polypeptide alpha-N-acetylgalactosaminyltransferase (pp-GalNAc-T10). J. Mol. Biol. 2006, 359, 708–727. [Google Scholar] [CrossRef]
  106. Raman, J.; Fritz, T.A.; Gerken, T.A.; Jamison, O.; Live, D.; Liu, M.; Tabak, L.A. The catalytic and lectin domains of UDP-GalNAc:polypeptide alpha-N-Acetylgalactosaminyltransferase function in concert to direct glycosylation site selection. J. Biol. Chem. 2008, 283, 22942–22951. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Mealer, R.G.; Williams, S.E.; Daly, M.J.; Scolnick, E.M.; Cummings, R.D.; Smoller, J.W. Glycobiology and schizophrenia: A biological hypothesis emerging from genomic research. Mol. Psychiatry 2020, 25, 3129–3139. [Google Scholar] [CrossRef]
  108. Gorski, M.; Tin, A.; Garnaas, M.; McMahon, G.M.; Chu, A.Y.; Tayo, B.O.; Pattaro, C.; Teumer, A.; Chasman, D.I.; Chalmers, J.; et al. Genome-wide association study of kidney function decline in individuals of European descent. Kidney Int. 2015, 87, 1017–1029. [Google Scholar] [CrossRef] [Green Version]
  109. Tian, E.; Wang, S.; Zhang, L.; Zhang, Y.; Malicdan, M.C.; Mao, Y.; Christoffersen, C.; Tabak, L.A.; Schjoldager, K.T.; Ten Hagen, K.G. Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding. Proc. Natl. Acad. Sci. USA 2019, 116, 25196–25202. [Google Scholar] [CrossRef]
  110. Fakhro, K.A.; Choi, M.; Ware, S.M.; Belmont, J.W.; Towbin, J.A.; Lifton, R.P.; Khokha, M.K.; Brueckner, M. Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Proc. Natl. Acad. Sci. USA 2011, 108, 2915–2920. [Google Scholar] [CrossRef] [Green Version]
  111. Al Dhaibani, M.A.; Allingham-Hawkins, D.; El-Hattab, A.W. De novo chromosome 7q36.1q36.2 triplication in a child with developmental delay, growth failure, distinctive facial features, and multiple congenital anomalies: A case report. BMC Med. Genet. 2017, 18, 118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Boskovski, M.T.; Yuan, S.; Pedersen, N.B.; Goth, C.K.; Makova, S.; Clausen, H.; Brueckner, M.; Khokha, M.K. The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature 2013, 504, 456–459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Guo, J.-M.; Zhang, Y.; Cheng, L.; Iwasaki, H.; Wang, H.; Kubota, T.; Tachibana, K.; Narimatsu, H. Molecular cloning and characterization of a novel member of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family, pp-GalNAc-T12. FEBS Lett. 2002, 524, 211–218. [Google Scholar] [CrossRef] [Green Version]
  114. Wang, Y.-N.; Zhou, X.-J.; Chen, P.; Yu, G.-Z.; Zhang, X.; Hou, P.; Liu, L.-J.; Shi, S.-F.; Lv, J.-C.; Zhang, H. Interaction between GALNT12 and C1GALNT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy. J. Am. Soc. Nephrol. 2021, 32, 545–552. [Google Scholar] [CrossRef] [PubMed]
  115. Hayashi, S.; Matsubara, T.; Fukuda, K.; Maeda, T.; Funahashi, K.; Hashimoto, M.; Kamenaga, T.; Takashima, Y.; Kuroda, R. A genome-wide association study identifying the SNPs predictive of rapid joint destruction in patients with rheumatoid arthritis. Biomed. Rep. 2021, 14, 31. [Google Scholar] [CrossRef]
  116. Hennet, T.; Hagen, F.K.; Tabak, L.A.; Marth, J.D. T-cell-specific deletion of a polypeptide N-acetylgalactosaminyl-transferase gene by site-directed recombination. Proc. Natl. Acad. Sci. USA 1995, 92, 12070–12074. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Milani, D.; Sabatini, C.; Manzoni, F.M.P.; Ajmone, P.F.; Rigamonti, C.; Malacarne, M.; Pierluigi, M.; Cavani, S.; Maria Antonella Costantino, M.A. Microdeletion 2q23.3q24.1: Exploring genotype-phenotype correlations. Congenit. Anom. 2015, 55, 107–111. [Google Scholar] [CrossRef] [Green Version]
  118. Wang, H.; Tachibana, K.; Zhang, Y.; Iwasaki, H.; Kameyama, A.; Cheng, L.; Guo, J.M.; Hiruma, T.; Togayachi, A.; Kudo, T.; et al. Cloning and characterization of a novel UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase, pp-GalNAc-T14. Biochem. Biophys. Res. Commun. 2003, 300, 738–744. [Google Scholar] [CrossRef]
  119. Shamseldin, H.E.; Tulbah, M.; Kurdi, W.; Nemer, M.; Alsahan, N.; Mardawi, E.A.; Khalifa, O.; Hashem, A.; Kurdi, A.; Babay, Z.; et al. Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. Genome Biol. 2015, 16, 116. [Google Scholar] [CrossRef] [Green Version]
  120. Karlslätt, K.S.; Pettersson, M.; Jäntti, N.; Szafranski, P.; Wester, T.; Husberg, B.; Ullberg, U.; Stankiewicz, P.; Nordgren, A.; Lundin, J.; et al. Rare copy number variants contribute pathogenic alleles in patients with intestinal malrotation. Mol. Genet. Genomic Med. 2019, 7, e549. [Google Scholar] [CrossRef] [Green Version]
  121. Froukh, T.; Hawwari, A. Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14. Curr. Mol. Med. 2019, 19, 683–687. [Google Scholar] [CrossRef]
  122. Cheng, L.; Tachibana, K.; Iwasaki, H.; Kameyama, A.; Zhang, Y.; Kubota, T.; Hiruma, T.; Tachibana, K.; Kudo, T.; Guo, J.-M.; et al. Characterization of a novel human UDP-GalNAc transferase, pp-GalNAc-T15. FEBS Lett. 2004, 566, 17–24. [Google Scholar] [CrossRef] [PubMed]
  123. Tabassum, R.; Rämö, J.T.; Ripatti, P.; Koskela, J.T.; Kurki, M.; Karjalainen, J.; Palta, P.; Hassan, S.; Nunez-Fontarnau, J.; Kiiskinen, T.T.J.; et al. Genetic architecture of human plasma lipidome and its link to cardiovascular disease. Nat. Commun. 2019, 10, 4329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Stringer, R.N.; Lazniewska, J.; Weiss, N. Transcriptomic analysis of glycan-processing genes in the dorsal root ganglia of diabetic mice and functional characterization on Ca v 3.2 channels. Channels 2020, 14, 132–140. [Google Scholar] [CrossRef] [Green Version]
  125. Peng, C.; Togayachi, A.; Kwon, Y.-D.; Xie, C.; Wu, G.; Zou, X.; Sato, T.; Ito, H.; Tachibana, K.; Kubota, T.; et al. Identification of a novel human UDP-GalNAc transferase with unique catalytic activity and expression profile. Biochem. Biophys. Res. Commun. 2010, 402, 680–686. [Google Scholar] [CrossRef]
  126. Ramírez, J.D.; Álvarez-Herms, J.; Castañeda-Babarro, A.; Larruskain, J.; de la Piscina, X.R.; Borisov, O.V.; Semenova, E.A.; Kostryukova, E.S.; Kulemin, N.A.; Andryushchenko, O.N.; et al. The GALNTL6 Gene rs558129 Polymorphism Is Associated With Power Performance. J. Strength Cond. Res. 2020, 34, 3031–3036. [Google Scholar] [CrossRef]
  127. Weisner, P.A.; Chen, C.-Y.; Sun, Y.; Yoo, J.; Kao, W.-C.; Zhang, H.; Baltz, E.T.; Troy, J.M.; Stubbs, L. A Mouse Mutation That Dysregulates Neighboring Galnt17 and Auts2 Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome. G3 2019, 9, 3891–3906. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Shan, A.; Lu, J.; Xu, Z.; Li, X.; Xu, Y.; Li, W.; Liu, F.; Yang, F.; Sato, T.; Narimatsu, H.; et al. Polypeptide N-acetylgalactosaminyltransferase 18 non-catalytically regulates the ER homeostasis and O-glycosylation. Biochim. Biophys. Acta Gen. Subj. 2019, 1863, 870–882. [Google Scholar] [CrossRef]
  129. Jia, W.; Zou, X.; Xu, Z.; Bai, L.; Shan, A.; Li, Y.; Shi, J.; Yang, F.; Ding, C.; Narimatsu, H.; et al. Polypeptide N-acetylgalactosaminyltransferase 18 Retains in Endoplasmic Reticulum Depending on its Luminal Regions Interacting with ER resident UGGT1, PLOD3 and LPCAT1. Glycobiology 2021. online ahead of print. [Google Scholar] [CrossRef]
  130. Coit, P.; Ortiz-Fernandez, L.; Lewis, E.E.; McCune, W.J.; Maksimowicz-McKinnon, K.; Sawalha, A.H. A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients. JCI Insight 2020, 5, e143654. [Google Scholar] [CrossRef]
  131. Nakamura, N.; Toba, S.; Hirai, M.; Morishita, S.; Mikami, T.; Konishi, M.; Itoh, N.; Kurosaka, A. Cloning and expression of a brain-specific putative UDP-GalNAc: Polypeptide N-acetylgalactosaminyltransferase gene. Biol. Pharm. Bull. 2005, 28, 429–433. [Google Scholar] [CrossRef] [Green Version]
  132. Takasaki, N.; Tachibana, K.; Ogasawara, S.; Matsuzaki, H.; Hagiuda, J.; Ishikawa, H.; Mochida, K.; Inoue, K.; Ogonuki, N.; Ogura, A.; et al. A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility. Proc. Natl. Acad. Sci. USA 2014, 111, 1120–1125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Wandall, H.H.; Nielsen, M.A.I.; King-Smith, S.; de Haan, N.; Bagdonaite, I. Global functions of O-glycosylation: Promises and challenges in O-glycobiology. FEBS J. 2021. online ahead of print. [Google Scholar] [CrossRef] [PubMed]
  134. Hussain, M.R.M.; Hoessli, D.C.; Fang, M. N-acetylgalactosaminyltransferases in cancer. Oncotarget 2016, 7, 54067–54081. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Molecules 26 05504 g001 550
Figure 1. GALNT3 and GalNAc-T3 mutations reported in HFTC patients. (A) Structure for the GALNT3 transcript (NM_004482.4) with positions of exons in the transcript. Note that exon1 is non-coding. Splice site variants are shown with the position in the corresponding introns. (B) The protein domain structure of GalNAc-T3 with the exon positions and LOF and missense mutations is shown. ex; exon.
Figure 1. GALNT3 and GalNAc-T3 mutations reported in HFTC patients. (A) Structure for the GALNT3 transcript (NM_004482.4) with positions of exons in the transcript. Note that exon1 is non-coding. Splice site variants are shown with the position in the corresponding introns. (B) The protein domain structure of GalNAc-T3 with the exon positions and LOF and missense mutations is shown. ex; exon.
Molecules 26 05504 g001
Table
Table 1. Summary of published GALNT2 mutations and associated phenotypes.
Table 1. Summary of published GALNT2 mutations and associated phenotypes.
#Nt Change (a)ExonConsequence (a)Domain AffectedGenotype StatusPhenotype (1)Reference
1c.[296dup]3p.[Tyr99*]StemHomozygoteGALNT2-CDG[43]
2c.[311T>C]3p.[Phe104Ser]CatalyticHomozygoteGALNT2-CDG[29]
3c.[598C>T]6p.[Arg200*]CatalyticHomozygoteGALNT2-CDG[43]
4c.[629G>C]7p.[Arg210Pro]CatalyticHomozygoteGALNT2-CDG[43]
5c.[865C>T]9p.[Gln289*]CatalyticHomozygoteGALNT2-CDG[29,43]
6c.[914A>C]10p.[Asp314Ala]CatalyticHeterozygote/HomozygoteAffected HDL-C levels (2)[27,29]
(a) Reference sequences: NM_004481.5. and NP_004472.1. Nomenclature according to (https://varnomen.hgvs.org/ accessed on 1 May 2020); Mutation names according to Mutalyzer website (https://mutalyzer.nl/ accessed on 15 March 2021). (1) The phenotype for GALNT2-congenital disorder of glycosylation (CDGIIt) refers to OMIM #61885 and that for affecting HDL-C levels refers to sources [27,29]. (2) GalNAc-T2D314A heterozygous mutation raised [27] and homozygous mutation lowered [29] plasma HDL-C levels in humans, for unknown reasons. #; number.
Table
Table 2. Summary of published GALNT3-related HFTC cases.
Table 2. Summary of published GALNT3-related HFTC cases.
FamilyAlleles (NM_004482.4) (a)AA Change (NP_004473.2) (a)EthnicitydbSNP Id# Family# CasesGenotype StatusReference
1c.[2T>A];[839G>A]p.[Met1Lys];[Cys280Tyr]TurkishNA;NA11Compound heterozygote[52]
2c.[485G>A];[485G>A] p.[Arg162Gln];[Arg162Gln]Turkishrs76671730511Homozygote[49]
3c.[539G>A;659T>A];[539G>A;659T>A]p.[Arg180His;Ile220Asn];[Arg180His;Ile220Asn]Chinesers77241024212Homozygote for 2 mutations[47]
4c.[767G>T];[767G>T]p.[Gly256Val];[Gly256Val]Caucasian, Norway (consang)NA12Homozygote[48]
5c.[782G>A];[782G>A]p.[Arg261Gln];[Arg261Gln]Iranianrs11187532111Homozygote[53]
6c.[815C>A];[1076C>A]p.[Thr272Lys];[Thr359Lys]Caucasianrs137853090/rs13785309111Compound heterozygote[54]
7c.[842A>G];[1097T>G]p.[Glu281Gly];[Leu366Arg]Indian, TamilNA/rs78044040112Compound heterozygote[55]
8c.[1245T>A];[1245T>A]p.[His415Gln];[His415Gln]TurkishNA11Homozygote[56]
9c.[1312C>T];[1774C>T]p.[Arg438Cys];[Gln592*]Caucasian (French/Canadian)rs1159208891/rs13785308711Compound heterozygote[57]
10c.[1312C>T];[1774C>T]p.[Arg438Cys];[Gln592*]NArs1159208891/rs13785308711Compound heterozygote[58]
11c.[1312C>T];[1312C>T]p.[Arg438Cys];[Arg438Cys]Pakistanirs76473069111Homozygote[56]
12c.[1313G>A];[1313G>A]p.[Arg438His];[Arg438His]Colombianrs115920889111Homozygote[59]
13c.[1319C>A];[484C>T]p.[Ala440Glu];[Arg162*] (1)Afro-Americanrs199930810/rs13785308611Compound heterozygote[60]
14c.[1681T>A];[1681T>A]p.[Cys561Ser];[Cys561Ser]IndianNA11Homozygote[61]
15c.[1720T>G];[1720T>G]p.[Cys574Gly];[Cys574Gly]Caucasian, Greekrs26760684111Homozygote[49]
16c.[484C>T];[484C>T]p.[Arg162*];[Arg162*]Africanrs13785308611Homozygote[62]
17c.[484C>T];[484C>T]p.[Arg162*];[Arg162*]Africanrs13785308611Homozygote[63]
18c.[966T>G];[1441C>T]p.[Tyr322*];[Gln481*]Caucasianrs137853088/rs13785308912Compound heterozygote[64]
19c.[1387A>T];[1387A>T]p.[Lys463*];[Lys463*]Caucasian, ItalyNA12Homozygote[65]
20c.[1460G>A];[1460G>A]p.[Trp487*];[Trp487*]TurkishNA11Homozygote[66]
21c.[1774C>T];[1774C>T]p.[Gln592*];[Gln592*]Caucasian (Northern European)rs13785308711Homozygote[67]
22c.[42_57del];[42_57del] (2)p.[Arg14Serfs*8];[Arg14Serfs*8]CaucasianNA11Homozygote[68]
23c.[254_255del];[254_255del]p.[Pro85Argfs*6];[Pro85Argfs*6]TurkishNA12Homozygote[69]
24c.[677del];[677del]p.[Ala226Valfs*3];[Ala226Valfs*3]Sri-Lankars78620525011Homozygote[49]
25c.[746_749del];[892del]p.[Val249Aspfs*8];[Tyr298Thrfs*5] (3)NArs774681591;rs77151064411Compound heterozygote[58]
26c.[746_749del];[746_749del]p.[Val249Aspfs*8];[Val249Aspfs*8]Caucasian (Portuguese)rs774681591 11Homozygote[70]
27c.[1102dup];[1102dup]p.[Ser368Phefs*8];[Ser368Phefs*8]IranianNA11Homozygote[66]
28c.[1584dup];[1584dup]p.[Pro529Thrfs*17];[Pro529Thrfs*17]NANA12Homozygote[58]
29c.[516-2A>T];[484C>T]p.[?];[Arg162*]Afro-Americanrs761396172/rs13785308613Compound heterozygote[71]
30c.[516-2A>T];[260_266del]p.[?];[Arg87Thrfs*19]NArs761396172/NA12Compound heterozygote[58]
31c.[516-2A>T];[1524+5G>A]p.[?]:[?]NArs761396172/rs37587948911Compound heterozygote[58]
32c.[516-2A>T];[516-2A>T]p.[?]:[?] (5)Africanrs76139617212Homozygote[72]
33c.[516-2A>G];[516-2A>G]p.[?]:[?]Caucasianrs76139617211Homozygote[73]
34c.[1524+1G>A];[1524+1G>A] (4)p.[?]:[?]Arabic-Lebanesers74565592411Homozygote[49]
35c.[1524+1G>A];[1524+1G>A]p.[?]:[?] (6)Arabic-Druzers76083086416Homozygote[46]
36c.[1524+1G>A];[1524+1G>A]p.[?]:[?]Arab-Israelirs76083086412Homozygote[74]
37c.[1524+1G>A];[1524+1G>A]p.[?]:[?]Jordanrs76083086411Homozygote[75]
38c.[1524+5G>A];[484C>T]p.[?];[Arg162*]Afro-Americanrs137853086/rs37587948917Compound heterozygote[46]
39c.[1626+1G>A];[803dup]p.[?];[Thr269Asnfs*3] (7) Caucasian (French)rs766750282;rs76675028211Compound heterozygote[76]
Total39 families62 cases
(a) Nomenclature according to <https://varnomen.hgvs.org/> accessed on 15 March 2021. Mutation names according to Mutalyzer website <https://mutalyzer.nl/> accessed on 1 May 2020; refseq: NM_004482.4. (1) Incorrectly named as A1319E and R484X [60]. (2) Named as nt position 41-58 [68]. (3) Incorrectly named as p.[Arg250Thrfs*2];[Tyr298Serfs*5] [47]. (4) Assigned as c.[1392+1G>A], but the chromatogram shows the sequence for ex8_ivs8 splice site region and the correct nomenclature for the mutation is c.[1524+1G>A]. (5) ex2 skipping was confirmed for c.[516-2A>T] allele. (6) ex8 skipping was confirmed for c.[1524+1G>A] allele. (7) ex9 skipping was confirmed for c.[1626+1G>A] allele.
Table
Table 3. GALNT3 mutations in HFTC and affected domains in GalNAc-T3.
Table 3. GALNT3 mutations in HFTC and affected domains in GalNAc-T3.
#Nt Change (NM_004482.4)ExonConsequenceDomain AffectedAlleles
1c.[2T>A]2p.[Met1Lys]Cytoplasmic1
2c.[485G>A]2p.[Arg162Gln]Catalytic2
3c.[539G>A;659T>A]3p.[Arg180His];[Ile220Asn]Catalytic2
4c.[767G>T]4p.[Gly256Val]Catalytic2
5c.[782G>A]4p.[Arg261Gln]Catalytic2
6c.[815C>A]4p.[Thr272Lys]Catalytic1
7c.[839G>A]5 splice sitep.[Cys280Tyr]Catalytic1
8c.[842A>G]5p.[Glu281Gly]Catalytic1
9c.[1076C>A]6p.[Thr359Lys]Catalytic1
10c.[1097T>G]6p.[Leu366Arg]Catalytic1
11c.[1245T>A]7p.[His415Gln]Catalytic2
12c.[1312C>T]7p.[Arg438Cys]Catalytic4
13c.[1313G>A]7p.[Arg438His]Catalytic2
14c.[1319C>A]7p.[Ala440Glu]Catalytic1
15c.[1681T>A]10p.[Cys561Ser]Lectin2
16c.[1720T>G]10p.[Cys574Gly]Lectin2
17c.[484C>T]2p.[Arg162*]Catalytic7
18c.[966T>G]5p.[Tyr322*]Catalytic1
19c.[1387A>T]7p.[Lys463*]Catalytic2
20c.[1441C>T]8p.[Gln481*]Catalytic1
21c.[1460G>A]8p.[Trp487*]Catalytic2
22c.[1774C>T]10p.[Gln592*]Lectin4
23c.[42_57del]2p.[Arg14Serfs*8]Cytoplasmic2
24c.[254_255del]2p.[Pro85Argfs*6]Stem2
25c.[260_266del]2p.[Arg87Thrfs*19]Stem1
26c.[677del]3p.[Ala226Valfs*3]Catalytic2
27c.[746_749del]4p.[Val249Aspfs*8]Catalytic3
28c.[803dup]4p.[Thr269Asnfs*3]Catalytic1
29c.[892del]5p.[Tyr298Thrfs*5]Catalytic1
30c.[1102dup]6p.[Ser368Phefs*8]Catalytic2
31c.[1584dup]9p.[Pro529Thrfs*17]Lectin2
32c.[516-2A>T]ivs2; ex2 skipping [72]p.[?]-3
33c.[516-2A>G]ivs2p.[?] or p.[Cys173Valfs*4]-4
34c.[1524+1G>A]ivs8; ex8 skipping [46]p.[?]-8
35c.[1524+5G>A]ivs8p.[?]-2
36c.[1626+1G>A]ivs9; ex9 skipping [76]p.[?]-1
Total number of alleles78
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Kato, K.; Hansen, L.; Clausen, H. Polypeptide N-acetylgalactosaminyltransferase-Associated Phenotypes in Mammals. Molecules 2021, 26, 5504. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185504

AMA Style

Kato K, Hansen L, Clausen H. Polypeptide N-acetylgalactosaminyltransferase-Associated Phenotypes in Mammals. Molecules. 2021; 26(18):5504. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185504

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Kato, Kentaro, Lars Hansen, and Henrik Clausen. 2021. "Polypeptide N-acetylgalactosaminyltransferase-Associated Phenotypes in Mammals" Molecules 26, no. 18: 5504. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185504

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