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Molecular Research in Medical Genetics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 50573

Special Issue Editor

Dr. Emanuela Viggiano

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Guest Editor
Prenatal Medicine, AULSS6-Euganea, Padua, Italy
Interests: Medical genetics; neuroscience; child obesity; alimentary; behaviour

Special Issue Information

Research in Medical Genetics is an important target to find the causes, inheritance and treatment of genetic disorders. To this aim, the molecular approach includes various techniques, including some new-generation ones that have showed very promising results.

This Special Issue on “Molecular Research in Medical Genetics” will cover a selection of recent research topics and current review articles related to molecular mechanisms in human genetic diseases. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Dr. Emanuela Viggiano
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • medical genetics
  • molecular research
  • metabolic disease
  • neuromuscular disease
  • obesity

Published Papers (12 papers)

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Editorial

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3 pages, 180 KiB  
Editorial
Molecular Research in Medical Genetics
by Emanuela Viggiano
Int. J. Mol. Sci. 2022, 23(12), 6625; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126625 - 14 Jun 2022
Cited by 1 | Viewed by 1002
Abstract
About 19,000–20,000 protein-coding genes in the human genome have been identified [...] Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)

Research

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13 pages, 1970 KiB  
Article
Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa
by Michael Ablinger, Thomas Lettner, Nicole Friedl, Hannah Potocki, Theresa Palmetzhofer, Ulrich Koller, Julia Illmer, Bernadette Liemberger, Stefan Hainzl, Alfred Klausegger, Manuela Reisenberger, Jo Lambert, Mireille Van Gele, Eline Desmet, Els Van Maelsaeke, Monika Wimmer, Roland Zauner, Johann W. Bauer and Verena Wally
Int. J. Mol. Sci. 2021, 22(7), 3326; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073326 - 24 Mar 2021
Cited by 11 | Viewed by 3232
Abstract
Intermediate junctional epidermolysis bullosa caused by mutations in the COL17A1 gene is characterized by the frequent development of blisters and erosions on the skin and mucous membranes. The rarity of the disease and the heterogeneity of the underlying mutations renders therapy developments challenging. [...] Read more.
Intermediate junctional epidermolysis bullosa caused by mutations in the COL17A1 gene is characterized by the frequent development of blisters and erosions on the skin and mucous membranes. The rarity of the disease and the heterogeneity of the underlying mutations renders therapy developments challenging. However, the high number of short in-frame exons facilitates the use of antisense oligonucleotides (AON) to restore collagen 17 (C17) expression by inducing exon skipping. In a personalized approach, we designed and tested three AONs in combination with a cationic liposomal carrier for their ability to induce skipping of COL17A1 exon 7 in 2D culture and in 3D skin equivalents. We show that AON-induced exon skipping excludes the targeted exon from pre-mRNA processing, which restores the reading frame, leading to the expression of a slightly truncated protein. Furthermore, the expression and correct deposition of C17 at the dermal–epidermal junction indicates its functionality. Thus, we assume AON-mediated exon skipping to be a promising tool for the treatment of junctional epidermolysis bullosa, particularly applicable in a personalized manner for rare genotypes. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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14 pages, 6737 KiB  
Article
Genetics and Genomics of SOST: Functional Analysis of Variants and Genomic Regulation in Osteoblasts
by Núria Martínez-Gil, Neus Roca-Ayats, Mónica Cozar, Natàlia Garcia-Giralt, Diana Ovejero, Xavier Nogués, Daniel Grinberg and Susanna Balcells
Int. J. Mol. Sci. 2021, 22(2), 489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020489 - 06 Jan 2021
Cited by 7 | Viewed by 2468
Abstract
SOST encodes the sclerostin protein, which acts as a key extracellular inhibitor of the canonical Wnt pathway in bone, playing a crucial role in skeletal development and bone homeostasis. The objective of this work was to assess the functionality of two variants previously [...] Read more.
SOST encodes the sclerostin protein, which acts as a key extracellular inhibitor of the canonical Wnt pathway in bone, playing a crucial role in skeletal development and bone homeostasis. The objective of this work was to assess the functionality of two variants previously identified (the rare variant rs570754792 and the missense variant p.Val10Ile) and to investigate the physical interactors of the SOST proximal promoter region in bone cells. Through a promoter luciferase reporter assay we show that the minor allele of rs570754792, a variant located in the extended TATA box motif, displays a significant decrease in promoter activity. Likewise, through western blot studies of extracellular and intracellular sclerostin, we observe a reduced expression of the p.Val10Ile mutant protein. Finally, using a circular chromosome conformation capture assay (4C-seq) in 3 bone cell types (MSC, hFOB, Saos-2), we have detected physical interactions between the SOST proximal promoter and the ECR5 enhancer, several additional enhancers located between EVT4 and MEOX1 and a distant region containing exon 18 of DHX8. In conclusion, SOST presents functional regulatory and missense variants that affect its expression and displays physical contacts with far reaching genomic sequences, which may play a role in its regulation within bone cells. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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16 pages, 4854 KiB  
Article
Four and a Half LIM Domains 2 (FHL2) Contribute to the Epithelial Ovarian Cancer Carcinogenesis
by Chen Wang, Xiangmin Lv, Chunbo He, John S. Davis, Cheng Wang and Guohua Hua
Int. J. Mol. Sci. 2020, 21(20), 7751; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207751 - 20 Oct 2020
Cited by 13 | Viewed by 2213
Abstract
Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies. To date, the etiology of this deadly disease remains elusive. FHL2, a member of the four and a half LIM domain family, has been shown to serve either as an oncoprotein [...] Read more.
Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies. To date, the etiology of this deadly disease remains elusive. FHL2, a member of the four and a half LIM domain family, has been shown to serve either as an oncoprotein or as a tumor suppressor in various cancers. Our previous study showed that FHL2 plays a critical role in the initiation and progression of ovarian granulosa cell tumor via regulating AKT1 transcription. However, direct and systematic evidence of FHL2 in the initiation and progression of EOC remains unclear. In the present study, immunohistochemical analysis from EOC patient tissues showed that positivity and intensity of FHL2 immunosignal were up-regulated in the EOC tissues compared with normal ovary tissues. Knockdown of FHL2 in SKOV-3 cell line reduced cell growth and cell viability, blocked cell cycle progression, and inhibited cell migration. Ectopic expression of FHL2 in IGROV-1 cells which have low endogenous FHL2, promoted cell growth, improved cell viability and enhanced cell migration. Additionally, knock down of FHL2 in the SKOV-3 cell line significantly inhibited anchorage-independent growth indicated by the soft agar assay. In comparison, overexpression of FHL2 in IGROV-1 cell improved the colonies growth in soft agar. Western blot data showed that knockdown of FHL2 downregulated AKT expression level, and upregulated apoptosis related proteins such as cleaved PARP, and cleaved-lamin A. Finally, by employing stable SKOV-3/FHL2 stable knock down cell line, our data clearly showed that knockdown of FHL2 inhibited EOC xenograft initiation in vivo. Taken together, our results showed that FHL2, via regulating cell proliferation, cell cycle, and adhesion, has a critical role in regulating EOC initiation and progression. These results indicate that FHL2 could be a potential target for the therapeutic drugs against EOC. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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Review

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17 pages, 2288 KiB  
Review
X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis
by Emanuela Viggiano and Luisa Politano
Int. J. Mol. Sci. 2021, 22(14), 7663; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147663 - 17 Jul 2021
Cited by 22 | Viewed by 3799
Abstract
Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where [...] Read more.
Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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18 pages, 16222 KiB  
Review
TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment
by Jeff Yat-Fai Chung, Max Kam-Kwan Chan, Jane Siu-Fan Li, Alex Siu-Wing Chan, Philip Chiu-Tsun Tang, Kam-Tong Leung, Ka-Fai To, Hui-Yao Lan and Patrick Ming-Kuen Tang
Int. J. Mol. Sci. 2021, 22(14), 7575; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147575 - 15 Jul 2021
Cited by 85 | Viewed by 13687
Abstract
Transforming growth factor-β (TGF-β) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor [...] Read more.
Transforming growth factor-β (TGF-β) signaling triggers diverse biological actions in inflammatory diseases. In tissue fibrosis, it acts as a key pathogenic regulator for promoting immunoregulation via controlling the activation, proliferation, and apoptosis of immunocytes. In cancer, it plays a critical role in tumor microenvironment (TME) for accelerating invasion, metastasis, angiogenesis, and immunosuppression. Increasing evidence suggest a pleiotropic nature of TGF-β signaling as a critical pathway for generating fibrotic TME, which contains numerous cancer-associated fibroblasts (CAFs), extracellular matrix proteins, and remodeling enzymes. Its pathogenic roles and working mechanisms in tumorigenesis are still largely unclear. Importantly, recent studies successfully demonstrated the clinical implications of fibrotic TME in cancer. This review systematically summarized the latest updates and discoveries of TGF-β signaling in the fibrotic TME. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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11 pages, 640 KiB  
Review
Correction of Heritable Epigenetic Defects Using Editing Tools
by Tayma Handal and Rachel Eiges
Int. J. Mol. Sci. 2021, 22(8), 3966; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083966 - 12 Apr 2021
Cited by 1 | Viewed by 2304
Abstract
Epimutations refer to mistakes in the setting or maintenance of epigenetic marks in the chromatin. They lead to mis-expression of genes and are often secondary to germline transmitted mutations. As such, they are the cause for a considerable number of genetically inherited conditions [...] Read more.
Epimutations refer to mistakes in the setting or maintenance of epigenetic marks in the chromatin. They lead to mis-expression of genes and are often secondary to germline transmitted mutations. As such, they are the cause for a considerable number of genetically inherited conditions in humans. The correction of these types of epigenetic defects constitutes a good paradigm to probe the fundamental mechanisms underlying the development of these diseases, and the molecular basis for the establishment, maintenance and regulation of epigenetic modifications in general. Here, we review the data to date, which is limited to repetitive elements, that relates to the applications of key editing tools for addressing the epigenetic aspects of various epigenetically regulated diseases. For each approach we summarize the efforts conducted to date, highlight their contribution to a better understanding of the molecular basis of epigenetic mechanisms, describe the limitations of each approach and suggest perspectives for further exploration in this field. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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17 pages, 1066 KiB  
Review
Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention
by Maria Teresa Vietri, Giovanna D’Elia, Gemma Caliendo, Marianna Resse, Amelia Casamassimi, Luana Passariello, Luisa Albanese, Michele Cioffi and Anna Maria Molinari
Int. J. Mol. Sci. 2021, 22(7), 3753; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073753 - 04 Apr 2021
Cited by 59 | Viewed by 8958
Abstract
Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared [...] Read more.
Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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20 pages, 2384 KiB  
Review
Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance
by Laura Fontana, Silvia Tabano, Silvia Maitz, Patrizia Colapietro, Emanuele Garzia, Alberto Giovanni Gerli, Silvia Maria Sirchia and Monica Miozzo
Int. J. Mol. Sci. 2021, 22(7), 3445; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073445 - 26 Mar 2021
Cited by 17 | Viewed by 4981
Abstract
Beckwith-Wiedemann syndrome (BWS) is a clinically and genetically heterogeneous overgrowth disease. BWS is caused by (epi)genetic defects at the 11p15 chromosomal region, which harbors two clusters of imprinted genes, IGF2/H19 and CDKN1C/KCNQ1OT1, regulated by differential methylation of imprinting [...] Read more.
Beckwith-Wiedemann syndrome (BWS) is a clinically and genetically heterogeneous overgrowth disease. BWS is caused by (epi)genetic defects at the 11p15 chromosomal region, which harbors two clusters of imprinted genes, IGF2/H19 and CDKN1C/KCNQ1OT1, regulated by differential methylation of imprinting control regions, H19/IGF2:IG DMR and KCNQ1OT1:TSS DMR, respectively. A subset of BWS patients show multi-locus imprinting disturbances (MLID), with methylation defects extended to other imprinted genes in addition to the disease-specific locus. Specific (epi)genotype-phenotype correlations have been defined in order to help clinicians in the classification of patients and referring them to a timely diagnosis and a tailored follow-up. However, specific phenotypic correlations have not been identified among MLID patients, thus causing a debate on the usefulness of multi-locus testing in clinical diagnosis. Finally, the high incidence of BWS monozygotic twins with discordant phenotypes, the high frequency of BWS among babies conceived by assisted reproductive technologies, and the female prevalence among BWS-MLID cases provide new insights into the timing of imprint establishment during embryo development. In this review, we provide an overview on the clinical and molecular diagnosis of single- and multi-locus BWS in pre- and post-natal settings, and a comprehensive analysis of the literature in order to define possible (epi)genotype-phenotype correlations in MLID patients. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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Other

9 pages, 2550 KiB  
Case Report
A New Intronic Variant in ECEL1 in Two Patients with Distal Arthrogryposis Type 5D
by Viola Alesi, Francesca Sessini, Silvia Genovese, Giusy Calvieri, Ester Sallicandro, Laura Ciocca, Maura Mingoia, Antonio Novelli and Paolo Moi
Int. J. Mol. Sci. 2021, 22(4), 2106; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042106 - 20 Feb 2021
Cited by 4 | Viewed by 2090
Abstract
Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the [...] Read more.
Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c.1507-9G>A), which was predicted to affect mRNA splicing by activating a cryptic acceptor site. The frequency of the variant is very low in the general human population, and its presence in our families can be attributed to a founder effect. This study provides an updated review of the known causative mutations of the ECEL1 gene, enriching the allelic spectrum to include the noncoding sequence. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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10 pages, 9232 KiB  
Case Report
De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family
by Laura Castilla-Vallmanya, Semra Gürsoy, Özlem Giray-Bozkaya, Aina Prat-Planas, Gemma Bullich, Leslie Matalonga, Mónica Centeno-Pla, Raquel Rabionet, Daniel Grinberg, Susanna Balcells and Roser Urreizti
Int. J. Mol. Sci. 2021, 22(4), 1549; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041549 - 04 Feb 2021
Cited by 4 | Viewed by 2326
Abstract
We present a Turkish family with two cousins (OC15 and OC15b) affected with syndromic developmental delay, microcephaly, and trigonocephaly but with some phenotypic traits distinct between them. OC15 showed asymmetrical skeletal defects and syndactyly, while OC15b presented with a more severe microcephaly and [...] Read more.
We present a Turkish family with two cousins (OC15 and OC15b) affected with syndromic developmental delay, microcephaly, and trigonocephaly but with some phenotypic traits distinct between them. OC15 showed asymmetrical skeletal defects and syndactyly, while OC15b presented with a more severe microcephaly and semilobal holoprosencephaly. All four progenitors were related and OC15 parents were consanguineous. Whole Exome Sequencing (WES) analysis was performed on patient OC15 as a singleton and on the OC15b trio. Selected variants were validated by Sanger sequencing. We did not identify any shared variant that could be associated with the disease. Instead, each patient presented a de novo heterozygous variant in a different gene. OC15 carried a nonsense mutation (p.Arg95*) in PORCN, which is a gene responsible for Goltz-Gorlin syndrome, while OC15b carried an indel mutation in ZIC2 leading to the substitution of three residues by a proline (p.His404_Ser406delinsPro). Autosomal dominant mutations in ZIC2 have been associated with holoprosencephaly 5. Both variants are absent in the general population and are predicted to be pathogenic. These two de novo heterozygous variants identified in the two patients seem to explain the major phenotypic alterations of each particular case, instead of a homozygous variant that would be expected by the underlying consanguinity. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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9 pages, 1716 KiB  
Case Report
Homozygous HESX1 and COL1A1 Gene Variants in a Boy with Growth Hormone Deficiency and Early Onset Osteoporosis
by Viola Alesi, Maria Lisa Dentici, Silvia Genovese, Sara Loddo, Emanuele Bellacchio, Valeria Orlando, Silvia Di Tommaso, Giorgia Catino, Chiara Calacci, Giusy Calvieri, Daniele Pompili, Graziamaria Ubertini, Bruno Dallapiccola, Rossella Capolino and Antonio Novelli
Int. J. Mol. Sci. 2021, 22(2), 750; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020750 - 13 Jan 2021
Cited by 1 | Viewed by 2290
Abstract
We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of homozygosity and two distinct homozygous variants in HESX1 (Q6H) and COL1A1 (E1361K) genes. The HESX1 variant [...] Read more.
We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of homozygosity and two distinct homozygous variants in HESX1 (Q6H) and COL1A1 (E1361K) genes. The HESX1 variant was described as causative in a few subjects with an incompletely penetrant dominant form of combined pituitary hormone deficiency (CPHD). The COL1A1 variant is rare, and so far it has never been found in a homozygous form. Segregation analysis showed that both variants were inherited from heterozygous unaffected parents. Present results further elucidate the inheritance pattern of HESX1 variants and recommend assessing the clinical impact of variants located in C-terminal propeptide of COL1A1 gene for their potential association with rare recessive and early onset forms of osteoporosis. Full article
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
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