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Genetics of Rare Disease
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Genetics of Rare Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (26 August 2021) | Viewed by 46235

Special Issue Editor

Prof. Dr. Lisbeth Birk Møller

E-Mail Website
Guest Editor
Applied Human Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University, Rigshospitalet, Glostrup, Denmark
Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, DK-4000, Roskilde, Denmark
Interests: primary cilia; Bardet–Biedl syndrome; RPE; iPSC; RT-PCR ; movement disorder; tuberous sclerosis

Special Issue Information

Dear Colleagues,

Individual rare disease affects few persons. There is no clear definition, but up to six persons per 10,000 is a good estimate. Because the total number of different rare diseases is extremely high, approximately 7000 of the total number of affected persons and families are quite high. Elucidating the disease-causing mechanisms behind all individual diseases leads to increased knowledge about how the normal body works and can thus contribute to the development of treatment for both rare and more frequent diseases.

In this Special Issue, we will focus on the group of rare diseases called ciliopathies. More precisely, we will focus on ciliopathies where the primary cilium is affected. These diseases include, but are not restricted to, Bardet–Biedl syndrome, nephronophthisis, cranioectodermal dysplasia, Joubert syndrome, Meckel–Gruber syndrome, oral–facial–digital syndrome, and short-rib polydactyly syndrome. We welcome submissions of reviews, research articles, short communications, and concept papers. 

Prof. Lisbeth Birk Møller
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. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • Primary cilia
  • Genetic disease
  • Cilia coordinated signaling
  • Syndromic
  • Pheno-genotype correlation
  • Diagnoses
  • Pathophysiological processes

Published Papers (13 papers)

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Research

Jump to: Review

16 pages, 2706 KiB  
Article
The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome
by Marite Punapart, Kadri Seppa, Toomas Jagomäe, Mailis Liiv, Riin Reimets, Silvia Kirillov, Allen Kaasik, Lieve Moons, Lies De Groef, Anton Terasmaa, Eero Vasar and Mario Plaas
Genes 2021, 12(11), 1717; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111717 - 28 Oct 2021
Cited by 2 | Viewed by 2089
Abstract
Wolfram syndrome (WS) 1 is a rare monogenic neurodegenerative disorder caused by mutations in the gene encoding WFS1. Knowledge of the pathophysiology of WS is incomplete and to date, there is no treatment available. Here, we describe early deviations in the renin-angiotensin-aldosterone system [...] Read more.
Wolfram syndrome (WS) 1 is a rare monogenic neurodegenerative disorder caused by mutations in the gene encoding WFS1. Knowledge of the pathophysiology of WS is incomplete and to date, there is no treatment available. Here, we describe early deviations in the renin-angiotensin-aldosterone system (RAAS) and bradykinin pathway (kallikrein kinin system, KKS) observed in a rat model of WS (Wfs1 KO) and the modulative effect of glucagon-like peptide-1 receptor agonist liraglutide (LIR) and anti-epileptic drug valproate (VPA), which have been proven effective in delaying WS progression in WS animal models. We found that the expression of key receptors of the RAAS and KKS, Agtr2 and Bdkrb1, were drastically downregulated both in vitro and in vivo at an early stage in a rat model of WS. Moreover, in Wfs1, KO serum aldosterone levels were substantially decreased and bradykinin levels increased compared to WT animals. Neither treatment nor their combination affected the gene expression levels seen in the Wfs1 KO animals. However, all the treatments elevated serum aldosterone and decreased bradykinin in the Wfs1 KO rats, as well as increasing angiotensin II levels independent of genotype. Altogether, our results indicate that Wfs1 deficiency might disturb the normal functioning of RAAS and KKS and that LIR and VPA have the ability to modulate these systems. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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14 pages, 3344 KiB  
Article
Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree
by Yuanzheng Feng, Jiewen Ma, Liang V Tang, Wenyi Lin, Yanyi Tao, Zhipeng Cheng and Yu Hu
Genes 2021, 12(10), 1521; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101521 - 27 Sep 2021
Viewed by 1936
Abstract
Background: Congenital coagulation factor X (FX) deficiency is a rare bleeding disorder with an incidence of one in one million caused by mutations in the FX-coding gene(F10), leading to abnormal coagulation activity and a tendency for severe hemorrhage. Therefore, identifying mutations in FX [...] Read more.
Background: Congenital coagulation factor X (FX) deficiency is a rare bleeding disorder with an incidence of one in one million caused by mutations in the FX-coding gene(F10), leading to abnormal coagulation activity and a tendency for severe hemorrhage. Therefore, identifying mutations in FX is important for diagnosing congenital FX deficiency. Results: Genetic analysis of the proband identified two single-base substitutions: c.794T > C: p.Ile265Thr and c.865 + 5G > A: IVS7 + 5G > A. His FX activity and antigen levels were < 1% and 49.7%, respectively; aPTT and PT were prolonged to 65.3 and 80.5 s, respectively. Bioinformatics analysis predicted the two novel variants to be pathogenic. In-vitro expression study of the missense mutation c.794T > C: p.Ile265Thr showed normal synthesis and secretion. Activation of FXs by RVV, FVII/TF, and FVIII/FIX all showed no obvious difference between the variant and the reference. However, clotting activity by PT and aPTT assays and activity of thrombin generation in a TGA assay all indicated reduced activity of the mutant FX-Ile265Thr compared to FX-WT. Minigene assay showed a normal splicing mode c.865 + 5G > A: IVS7 + 5G > A, which is inconsistent with clinical phenotype. Conclusions: The heterozygous variants c.794T > C: p.Ile265Thr or c.865 + 5G > A: IVS7 + 5G > A indicate mild FX deficiency, but the compound heterozygous mutation of the two causes severe congenital FX deficiency. Genetic analysis of these two mutations may help characterize the bleeding tendency and confirm congenital FX deficiency. In-vitro expression and functional study showed that the low activity of the mutant FX-Ile265Thr is caused by decrease in its enzyme activity rather than self-activation. The minigene assay help us explore possible mechanisms of the splicing mutation. However, more in-depth mechanism research is needed in the future. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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19 pages, 6462 KiB  
Article
Novel Approach Combining Transcriptional and Evolutionary Signatures to Identify New Multiciliation Genes
by Audrey Defosset, Dorine Merlat, Laetitia Poidevin, Yannis Nevers, Arnaud Kress, Olivier Poch and Odile Lecompte
Genes 2021, 12(9), 1452; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091452 - 21 Sep 2021
Cited by 2 | Viewed by 2097
Abstract
Multiciliogenesis is a complex process that allows the generation of hundreds of motile cilia on the surface of specialized cells, to create fluid flow across epithelial surfaces. Dysfunction of human multiciliated cells is associated with diseases of the brain, airway and reproductive tracts. [...] Read more.
Multiciliogenesis is a complex process that allows the generation of hundreds of motile cilia on the surface of specialized cells, to create fluid flow across epithelial surfaces. Dysfunction of human multiciliated cells is associated with diseases of the brain, airway and reproductive tracts. Despite recent efforts to characterize the transcriptional events responsible for the differentiation of multiciliated cells, a lot of actors remain to be identified. In this work, we capitalize on the ever-growing quantity of high-throughput data to search for new candidate genes involved in multiciliation. After performing a large-scale screening using 10 transcriptomics datasets dedicated to multiciliation, we established a specific evolutionary signature involving Otomorpha fish to use as a criterion to select the most likely targets. Combining both approaches highlighted a list of 114 potential multiciliated candidates. We characterized these genes first by generating protein interaction networks, which showed various clusters of ciliated and multiciliated genes, and then by computing phylogenetic profiles. In the end, we selected 11 poorly characterized genes that seem like particularly promising multiciliated candidates. By combining functional and comparative genomics methods, we developed a novel type of approach to study biological processes and identify new promising candidates linked to that process. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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13 pages, 1245 KiB  
Article
The Association of ATG16L1 Variations with Clinical Phenotypes of Adult-Onset Still’s Disease
by Wei-Ting Hung, Shuen-Iu Hung, Yi-Ming Chen, Chia-Wei Hsieh, Hsin-Hua Chen, Kuo-Tung Tang, Der-Yuan Chen and Tsuo-Hung Lan
Genes 2021, 12(6), 904; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060904 - 11 Jun 2021
Cited by 4 | Viewed by 2132
Abstract
Adult-onset Still’s disease (AOSD) is a rare autoinflammatory disease, which has elevated autophagosome levels regulated by autophagy-related gene (ATG) expression. We investigated the associations of ATG polymorphisms with AOSD susceptibility, clinical manifestations, and disease course. The six-candidate single-nucleotide polymorphisms (SNPs) involved in autophagy [...] Read more.
Adult-onset Still’s disease (AOSD) is a rare autoinflammatory disease, which has elevated autophagosome levels regulated by autophagy-related gene (ATG) expression. We investigated the associations of ATG polymorphisms with AOSD susceptibility, clinical manifestations, and disease course. The six-candidate single-nucleotide polymorphisms (SNPs) involved in autophagy were genotyped using direct sequencing on samples from 129 AOSD patients and 129 healthy participants. The differentially expressed gene products were quantified using PCR and ELISA. Significant linkage disequilibrium was noted in three SNPs of autophagy-related 16-like 1 (ATG16L1) gene (rs10210302, rs2241880, and rs1045100). Although the AA/CC/TT haplotype of ATG16L1 was not associated with the susceptibility of our AOSD patients compared with other haplotypes, those carrying this haplotype had lower mRNA expression levels of LC3-II, reflecting by autophagosome formation (p = 0.026). Patients carrying AA/CC/TT haplotype also have a significantly higher proportion of skin rash and a lower proportion of arthritis compared with other haplotypes. The AA/CC/TT haplotype was significantly associated with systemic pattern (odds ratio, 3.25; 95% confidence interval, 1.15–9.14; p = 0.026). In summary, the AA/CC/TT haplotype encoded lower levels of autophagosome formation and was associated with a higher proportion of skin rash and systemic pattern of AOSD compared with other haplotypes. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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13 pages, 2065 KiB  
Article
A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome
by Isabel Schüle, Urs Berger, Uta Matysiak, Gunda Ruzaike, Brigitte Stiller, Martin Pohl, Ute Spiekerkoetter, Ekkehart Lausch, Sarah C. Grünert and Miriam Schmidts
Genes 2021, 12(6), 879; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060879 - 07 Jun 2021
Cited by 23 | Viewed by 3088
Abstract
Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation syndrome. Pathogenic variants in HAAO (3-Hydroxyanthranilate 3,4-dioxygenase), NADSYN1 (NAD+ Synthetase-1) and KYNU (Kynureninase) have been identified in a handful of affected individuals. All three genes encode for enzymes essential [...] Read more.
Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation syndrome. Pathogenic variants in HAAO (3-Hydroxyanthranilate 3,4-dioxygenase), NADSYN1 (NAD+ Synthetase-1) and KYNU (Kynureninase) have been identified in a handful of affected individuals. All three genes encode for enzymes essential for the NAD+ de novo synthesis pathway. Using Trio-Exome analysis and CGH array analysis in combination with long range PCR, we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU in an individual presenting with overlapping features of VCRL and Catel–Manzke Syndrome. Interestingly, only the mother, not the father carried the small deletion in a heterozygous state. High-resolution SNP array analysis subsequently delineated a maternal isodisomy of chromosome 2 (UPD2). Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis. Our findings confirm the clinical, genetic and metabolic phenotype of VCRL1, adding a novel functionally tested disease allele. We also describe the first patient with NAD+ deficiency disorder resulting from a UPD. Furthermore, we provide a comprehensive review of the current literature covering the genetic basis and pathomechanisms for VCRL and Catel–Manzke Syndrome, including possible phenotype/genotype correlations as well as genetic causes of hypoplastic left heart syndrome. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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18 pages, 3865 KiB  
Article
Whole-Exome Sequencing, Proteome Landscape, and Immune Cell Migration Patterns in a Clinical Context of Menkes Disease
by Margarita L. Martinez-Fierro, Griselda A. Cabral-Pacheco, Idalia Garza-Veloz, Jesus Acuña-Quiñones, Laura E. Martinez-de-Villarreal, Marisol Ibarra-Ramirez, Joke Beuten, Samantha E. Sanchez-Guerrero, Laura Villarreal-Martinez, Ivan Delgado-Enciso, Iram P. Rodriguez-Sanchez, Vania Z. Zuñiga-Ramirez, Edith Cardenas-Vargas and Viktor Romero-Diaz
Genes 2021, 12(5), 744; https://doi.org/10.3390/genes12050744 - 14 May 2021
Cited by 2 | Viewed by 2416
Abstract
Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α (ATP7A) gene. Our objective was to identify genomic alterations and circulating [...] Read more.
Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α (ATP7A) gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the ATP7A gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins (p = 9.44 × 10−11). Additional studies are necessary to validate these findings as hallmarks of MD. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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8 pages, 233 KiB  
Article
Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG)
by Eu Jeen Yang, Ye Jee Shim, Heung Sik Kim, Young Tak Lim, Ho Joon Im, Kyung-Nam Koh, Hyery Kim, Jin Kyung Suh, Eun Sil Park, Na Hee Lee, Young Bae Choi, Jeong Ok Hah, Jae Min Lee, Jung Woo Han, Jae Hee Lee, Young-Ho Lee, Hye Lim Jung, Jung-Sook Ha, Chang-Seok Ki and on behalf of the Benign Hematology Committee of the Korean Pediatric Hematology Oncology Group (KPHOG)
Genes 2021, 12(5), 693; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050693 - 06 May 2021
Cited by 2 | Viewed by 2592
Abstract
The diagnosis of inherited platelet function disorders (IPFDs) is challenging owing to the unavailability of essential testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. This study, conducted by the Korean Pediatric Hematology Oncology Group from March [...] Read more.
The diagnosis of inherited platelet function disorders (IPFDs) is challenging owing to the unavailability of essential testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. This study, conducted by the Korean Pediatric Hematology Oncology Group from March 2017 to December 2020, aimed to identify the causative genetic variants of IPFDs in Korean patients using next-generation sequencing (NGS). Targeted exome sequencing, followed by whole-genome sequencing, was performed for diagnosing IPFDs. Of the 11 unrelated patients with suspected IPFDs enrolled in this study, 10 patients and 2 of their family members were diagnosed with Glanzmann thrombasthenia (GT). The variant c.1913+5G>T of ITGB3 was the most common, followed by c.2333A>C (p.Gln778Pro) of ITGB2B. Known variants of GT, including c.917A>C (p.His306Pro) of ITGB3 and c.2975del (p.Glu992Glyfs*), c.257T>C (p.Leu86Pro), and c.1750C>T (p.Arg584*) of ITGA2B, were identified. Four novel variants of GT, c.1451G>T (p.Gly484Val) and c.1595G>T (p.Cys532Phe) of ITGB3 and c.1184G>T (p.Gly395Val) and c.2390del (p.Gly797Valfs*29) of ITGA2B, were revealed. The remaining patient was diagnosed with platelet type bleeding disorder 18 and harbored two novel RASGRP2 variants, c.1479dup (p.Arg494Alafs*54) and c.813+1G>A. We demonstrated the successful application of NGS for the accurate and differential diagnosis of heterogeneous IPFDs. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
14 pages, 1770 KiB  
Article
Generating New FANCA-Deficient HNSCC Cell Lines by Genomic Editing Recapitulates the Cellular Phenotypes of Fanconi Anemia
by Ricardo Errazquin, Esther Sieiro, Pilar Moreno, María José Ramirez, Corina Lorz, Jorge Peral, Jessica Ortiz, José Antonio Casado, Francisco J. Roman-Rodriguez, Helmut Hanenberg, Paula Río, Jordi Surralles, Carmen Segrelles and Ramon Garcia-Escudero
Genes 2021, 12(4), 548; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040548 - 09 Apr 2021
Cited by 2 | Viewed by 4392
Abstract
Fanconi anemia (FA) patients have an exacerbated risk of head and neck squamous cell carcinoma (HNSCC). Treatment is challenging as FA patients display enhanced toxicity to standard treatments, including radio/chemotherapy. Therefore, better therapies as well as new disease models are urgently needed. We [...] Read more.
Fanconi anemia (FA) patients have an exacerbated risk of head and neck squamous cell carcinoma (HNSCC). Treatment is challenging as FA patients display enhanced toxicity to standard treatments, including radio/chemotherapy. Therefore, better therapies as well as new disease models are urgently needed. We have used CRISPR/Cas9 editing tools in order to interrupt the human FANCA gene by the generation of insertions/deletions (indels) in exon 4 in two cancer cell lines from sporadic HNSCC having no mutation in FA-genes: CAL27 and CAL33 cells. Our approach allowed efficient editing, subsequent purification of single-cell clones, and Sanger sequencing validation at the edited locus. Clones having frameshift indels in homozygosis did not express FANCA protein and were selected for further analysis. When compared with parental CAL27 and CAL33, FANCA-mutant cell clones displayed a FA-phenotype as they (i) are highly sensitive to DNA interstrand crosslink (ICL) agents such as mitomycin C (MMC) or cisplatin, (ii) do not monoubiquitinate FANCD2 upon MMC treatment and therefore (iii) do not form FANCD2 nuclear foci, and (iv) they display increased chromosome fragility and G2 arrest after diepoxybutane (DEB) treatment. These FANCA-mutant clones display similar growth rates as their parental cells. Interestingly, mutant cells acquire phenotypes associated with more aggressive disease, such as increased migration in wound healing assays. Therefore, CAL27 and CAL33 cells with FANCA mutations are phenocopies of FA-HNSCC cells. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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16 pages, 2735 KiB  
Article
Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development
by Jeremy W. Prokop, Caleb P. Bupp, Austin Frisch, Stephanie M. Bilinovich, Daniel B. Campbell, Daniel Vogt, Chad R. Schultz, Katie L. Uhl, Elizabeth VanSickle, Surender Rajasekaran and André S. Bachmann
Genes 2021, 12(4), 470; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040470 - 25 Mar 2021
Cited by 12 | Viewed by 5604
Abstract
Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood [...] Read more.
Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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13 pages, 1607 KiB  
Article
Pancytopenia, Recurrent Infection, Poor Wound Healing, Heterotopia of the Brain Probably Associated with A Candidate Novel de Novo CDC42 Gene Defect: Expanding the Molecular and Phenotypic Spectrum
by Abdulaziz Asiri, Deemah Alwadaani, Muhammad Umair, Kheloud M. Alhamoudi, Mohammed H. Almuhanna, Abdul Nasir, Bahauddeen M. Alrfaei, Abeer Al Tuwaijri, Tlili Barhoumi, Yusra Alyafee, Bader Almuzzaini, Mohammed Aldrees, Mariam Ballow, Latifah Alayyar, Abdulkareem Al Abdulrahman, Yazeid Alhaidan, Nahlah Al Ghasham, Sulaiman Al-Ajaji, Mohammad Alsalamah, Wafa Al Suwairi and Majid Alfadheladd Show full author list remove Hide full author list
Genes 2021, 12(2), 294; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020294 - 20 Feb 2021
Cited by 10 | Viewed by 2659
Abstract
CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology [...] Read more.
CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the CDC42 gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of CDC42 pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the CDC42 gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the CDC42 gene associated with aberrant cell migration and immune response. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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Review

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44 pages, 5552 KiB  
Review
Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease
by Shabarni Gupta, Justyna E. Ozimek-Kulik and Jacqueline Kathleen Phillips
Genes 2021, 12(11), 1762; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111762 - 05 Nov 2021
Cited by 11 | Viewed by 7250
Abstract
The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted [...] Read more.
The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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17 pages, 1308 KiB  
Review
Catalogue for Transmission Genetics in Arabs (CTGA) Database: Analysing Lebanese Data on Genetic Disorders
by Sami Bizzari, Pratibha Nair, Asha Deepthi, Sayeeda Hana, Mahmoud Taleb Al-Ali, André Megarbané and Stephany El-Hayek
Genes 2021, 12(10), 1518; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101518 - 27 Sep 2021
Cited by 6 | Viewed by 2273
Abstract
Lebanon has a high annual incidence of birth defects at 63 per 1000 live births, most of which are due to genetic factors. The Catalogue for Transmission Genetics in Arabs (CTGA) database, currently holds data on 642 genetic diseases and 676 related genes, [...] Read more.
Lebanon has a high annual incidence of birth defects at 63 per 1000 live births, most of which are due to genetic factors. The Catalogue for Transmission Genetics in Arabs (CTGA) database, currently holds data on 642 genetic diseases and 676 related genes, described in Lebanese subjects. A subset of disorders (14/642) has exclusively been described in the Lebanese population, while 24 have only been reported in CTGA and not on OMIM. An analysis of all disorders highlights a preponderance of congenital malformations, deformations and chromosomal abnormalities and demonstrates that 65% of reported disorders follow an autosomal recessive inheritance pattern. In addition, our analysis reveals that at least 58 known genetic disorders were first mapped in Lebanese families. CTGA also hosts 1316 variant records described in Lebanese subjects, 150 of which were not reported on ClinVar or dbSNP. Most variants involved substitutions, followed by deletions, duplications, as well as in-del and insertion variants. This review of genetic data from the CTGA database highlights the need for screening programs, and is, to the best of our knowledge, the most comprehensive report on the status of genetic disorders in Lebanon to date. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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31 pages, 12662 KiB  
Review
Using Paramecium as a Model for Ciliopathies
by Megan Valentine and Judith Van Houten
Genes 2021, 12(10), 1493; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101493 - 24 Sep 2021
Cited by 8 | Viewed by 6021
Abstract
Paramecium has served as a model organism for the studies of many aspects of genetics and cell biology: non-Mendelian inheritance, genome duplication, genome rearrangements, and exocytosis, to name a few. However, the large number and patterning of cilia that cover its surface have [...] Read more.
Paramecium has served as a model organism for the studies of many aspects of genetics and cell biology: non-Mendelian inheritance, genome duplication, genome rearrangements, and exocytosis, to name a few. However, the large number and patterning of cilia that cover its surface have inspired extraordinary ultrastructural work. Its swimming patterns inspired exquisite electrophysiological studies that led to a description of the bioelectric control of ciliary motion. A genetic dissection of swimming behavior moved the field toward the genes and gene products underlying ciliary function. With the advent of molecular technologies, it became clear that there was not only great conservation of ciliary structure but also of the genes coding for ciliary structure and function. It is this conservation and the legacy of past research that allow us to use Paramecium as a model for cilia and ciliary diseases called ciliopathies. However, there would be no compelling reason to study Paramecium as this model if there were no new insights into cilia and ciliopathies to be gained. In this review, we present studies that we believe will do this. For example, while the literature continues to state that immotile cilia are sensory and motile cilia are not, we will provide evidence that Paramecium cilia are clearly sensory. Other examples show that while a Paramecium protein is highly conserved it takes a different interacting partner or conducts a different ion than expected. Perhaps these exceptions will provoke new ideas about mammalian systems. Full article
(This article belongs to the Special Issue Genetics of Rare Disease)
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