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Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis

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

Deadline for manuscript submissions: closed (15 June 2021) | Viewed by 15146

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Special Issue Editor

Dr. Dorottya Csuka

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Guest Editor

Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
Interests: complement system; C3-glomerulopathy; hemolytic uremic syndrome; hereditary angioedema

Special Issue Information

Dear Colleagues,

Since the first DNA sequences were generated back in the 1970s by Ray Wu (Cornell University), by Walter Gilbert and Allan Maxam (Harvard University), as well as by Frederick Sanger (MRC Centre, Cambridge), exploring the DNA sequence of interest has become indispensable for a wide range of professions, such as medical diagnosis, molecular biology research, microbiology, forensic biology, etc. Although the most widespread method, Sanger-sequencing has been the “gold standard” for decades, the advent of next generation sequencing methods enabled the robust and fast sequencing of entire genomes, including the human genome and further complete DNA substances of many animal, plant, or microbial species.

Nowadays, scientists may detect easily a large proportion of disease-causing mutations, in the background of various disorders, such as cancers or (rare) hereditary diseases, enabling a more individualized treatment strategy.

The proposed Special Issue entitled “Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis” aims to present novel disease-associated candidate genes, genetic variations of potential diagnostic value and possible pioneering therapeutic approaches. For this purpose, a wide range of publications by experts in the above mentioned issues are welcome, in the form of original research papers.

Dr. Dorottya Csuka
Guest Editor

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Keywords

molecular genetic diagnosis
(rare) hereditary disorders
risk variations
novel therapeutic approaches

Published Papers (6 papers)

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Research

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7 pages, 1162 KiB

Open AccessArticle

MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease

by Nadine Maier, Constantin Gatterer, Patrick Haider, Manuel Salzmann, Christoph Kaun, Walter S. Speidl, Gere Sunder-Plassmann, Bruno K. Podesser, Johann Wojta, Senta Graf, Max Lenz and Philipp J. Hohensinner

Genes 2021, 12(8), 1184; https://doi.org/10.3390/genes12081184 - 30 Jul 2021

Cited by 4 | Viewed by 2095

Abstract

Background: Fabry disease is a hereditary genetic defect resulting in reduced activity of the enzyme α-galactosidase-A and the accumulation of globotriaosylceramide (Gb3) in body fluids and cells. Gb3 accumulation was especially reported for the vascular endothelium in several organs. Methods: Three Fabry disease patients were screened using a micro-RNA screen. An in vitro approach in human endothelial cells was used to determine miRNA regulation by Gb3. Results: In a micro-RNA screen of three Fabry patients undergoing enzyme replacement therapy, we found that miRNAs let-7a and let-7d were significantly increased after therapy. We demonstrate in vitro in endothelial cells that Gb3 induced activation of NF-κB and activated downstream targets. In addition, NF-κB activity directly reduced let-7a and let-7d miRNA expression as inhibiting NF-kB nuclear entry abolished the Gb3 effects. Conclusion: We suggest that let-7a and let-7d are potential markers for enzyme activity and inflammation in Fabry disease patients. Full article

(This article belongs to the Special Issue Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis)

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12 pages, 7086 KiB

Open AccessArticle

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features

by Zoltán Pozsonyi, Gergely Peskó, Hedvig Takács, Dorottya Csuka, Viktória Nagy, Ágnes Szilágyi, Lidia Hategan, Balázs Muk, Beáta Csányi, Noémi Nyolczas, Lívia Dézsi, Judit Mária Molnár, Anita Csillik, Katalin Révész, Béla Iványi, Fruzsina Szabó, Krisztián Birtalan, Tamás Masszi, Zsuzsanna Arányi and Róbert Sepp

Genes 2021, 12(8), 1152; https://doi.org/10.3390/genes12081152 - 28 Jul 2021

Cited by 6 | Viewed by 2154

Abstract

Background: Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited disease, where the mutation of the transthyretin gene (TTR) results in the deposition of pathogenic protein fibrils in various tissues. The mutation type influences the clinical course. Until now, no data were available on the genotype, phenotype, and prevalence of Hungarian ATTRv patients. The aim of our study was to assess the prevalence, regional distribution, genotypes, and phenotypes of Hungarian patients with ATTRv. Methods: With the collaboration of Hungarian regional and university centers, we identified patients diagnosed with ATTRv. We also searched prior publications for case studies of Hungarian ATTRv patients. Results: 40 individuals in 23 families with ATTRv were identified within the borders of Hungary. At the time of the diagnosis, 24 of them were symptomatic. The two most common mutations were ATTRHis88Arg (nine families) and ATTRIle107Val (8 families). ATTRVal30Met was demonstrated in 2 families, and ATTRVal122del, ATTRPhe33Leu, ATTRIle84Ser, and ATTRAsp18Gly in one family each. The median age of the symptomatic patients at the time of clinical diagnosis was 65 years. The most common clinically significant organ involvement was restrictive cardiomyopathy, found in 24 patients. Polyneuropathy was diagnosed in 20 patients. A total of 19 patients showed a mixed phenotype. The leading symptom was heart failure in 8 cases (3 of them had only cardiac symptoms), polyneuropathy in 11 cases (all of them also had cardiac symptoms), and equally severe cardiac and neuropathy symptoms were present in 3 cases. Out of 24 symptomatic patients, 10 received targeted pharmacological therapy. The follow-up period ranged from 1 to 195 months. At the time of the retrospective analysis, 12 patients had already died, and 1 patient underwent heart transplantation. Conclusions: As TTR genotype influences the phenotype and clinical course of ATTRv, it is important to know the regional data. In Hungary, ATTRHis88Arg and ATTRIle107Val are the most common mutations in ATTRv, both presenting with mixed phenotype, but the median age at the time of the diagnosis is 9 years lower in patients with ATTRHis88Arg than in patients with ATTRIle107Val. Full article

(This article belongs to the Special Issue Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis)

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14 pages, 925 KiB

Open AccessArticle

Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

by Donato Gemmati, Giovanna Longo, Eugenia Franchini, Juliana Araujo Silva, Ines Gallo, Barbara Lunghi, Stefano Moratelli, Iva Maestri, Maria Luisa Serino and Veronica Tisato

Genes 2021, 12(6), 934; https://doi.org/10.3390/genes12060934 - 18 Jun 2021

Cited by 10 | Viewed by 2790

Abstract

Inherited thrombophilia (e.g., venous thromboembolism, VTE) is due to rare loss-of-function mutations in anticoagulant factors genes (i.e., SERPINC1, PROC, PROS1), common gain-of-function mutations in procoagulant factors genes (i.e., F5, F2), and acquired risk conditions. Genome Wide Association Studies (GWAS) recently recognized several genes associated with VTE though gene defects may unpredictably remain asymptomatic, so calculating the individual genetic predisposition is a challenging task. We investigated a large family with severe, recurrent, early-onset VTE in which two sisters experienced VTE during pregnancies characterized by a perinatal in-utero thrombosis in the newborn and a life-saving pregnancy-interruption because of massive VTE, respectively. A nonsense mutation (CGA > TGA) generating a premature stop-codon (c.1171C>T; p.R391*) in the exon 6 of SERPINC1 gene (1q25.1) causing Antithrombin (AT) deficiency and the common missense mutation (c.1691G>A; p.R506Q) in the exon 10 of F5 gene (1q24.2) (i.e., FV Leiden; rs6025) were coinherited in all the symptomatic members investigated suspecting a cis-segregation further confirmed by STR-linkage-analyses [i.e., SERPINC1 IVS5 (ATT)_5–18, F5 IVS2 (AT)_6–33 and F5 IVS11 (GT)_12–16] and SERPINC1 intragenic variants (i.e., rs5878 and rs677). A multilocus investigation of blood-coagulation balance genes detected the coexistence of FV Leiden (rs6025) in trans with FV HR2-haplotype (p.H1299R; rs1800595) in the aborted fetus, and F11 rs2289252, F12 rs1801020, F13A1 rs5985, and KNG1 rs710446 in the newborn and other members. Common selected gene variants may strongly synergize with less common mutations tuning potential life-threatening conditions when combined with rare severest mutations. Merging classic and newly GWAS-identified gene markers in at risk families is mandatory for VTE risk estimation in the clinical practice, avoiding partial risk score evaluation in unrecognized at risk patients. Full article

(This article belongs to the Special Issue Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis)

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6 pages, 694 KiB

Open AccessArticle

Screening for Plasminogen Mutations in Hereditary Angioedema Patients

by Henriette Farkas, Anna Dóczy, Edina Szabó, Lilian Varga and Dorottya Csuka

Genes 2021, 12(3), 402; https://doi.org/10.3390/genes12030402 - 11 Mar 2021

Cited by 5 | Viewed by 2432

Abstract

Hereditary angioedema (HAE) is a rare disease belonging to the group of bradykinin-mediated angioedemas, characterized by recurring edematous episodes involving the subcutaneous and/or submucosal tissues. Most cases of HAE are caused by mutations in the SERPING1 gene encoding C1-inhibitor (C1-INH-HAE); however, mutation analysis identified seven further types of HAE: HAE with Factor XII mutation (FXII-HAE), with plasminogen gene mutation (PLG-HAE), with angiopoietin-1 gene mutation (ANGPT1-HAE), with kininogen-1 gene mutation (KNG1-HAE), with a myoferlin gene mutation (MYOF-HAE), with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation, and hereditary angioedema of unknown origin (U-HAE). We sequenced DNA samples stored from 124 U-HAE patients in the biorepository for exon 9 of the PLG gene. One of the 124 subjects carried the mutation causing a lysine to glutamic acid amino acid exchange at position 330 (K330E). Later, the same PLG mutation was identified in the patient’s son. The introduction of new techniques into genetic testing has increased the number of genes identified. As shown by this study, a biorepository creates the means for the ex-post analysis of recently identified genes in stored DNA samples of the patients. This makes the diagnosis more accurate with the possibility of subsequent family screening and the introduction of appropriate therapy. Full article

(This article belongs to the Special Issue Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis)

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10 pages, 2204 KiB

Open AccessArticle

Simultaneous Homozygous Mutations in SLC12A3 and CLCNKB in an Inbred Chinese Pedigree

by Lijun Mou and Fengfen Wu

Genes 2021, 12(3), 369; https://doi.org/10.3390/genes12030369 - 5 Mar 2021

Cited by 8 | Viewed by 1938

Abstract

Gitelman syndrome (GS) and Bartter syndrome (BS) type III are both rare, recessively inherited salt-losing tubulopathies caused by SLC12A3 and CLCNKB mutations, respectively. We described a 48-year-old male patient with fatigue, carpopedal spasm, arthralgia, hypokalemic alkalosis, mild renal dysfunction, hypomagnesemia, hypocalciuria, hyperuricemia, normotension, hyperreninemia and chondrocalcinosis in knees and Achilles tendons. His parents are first cousin. Genetic analysis revealed simultaneous homozygous mutations in SLC12A3 gene with c.248G>A, p.Arg83Gln and CLCNKB gene with c.1171T>C, p.Trp391Arg. The second younger brother of the proband harbored the same simultaneous mutations in SLC12A3 and CLCNKB and exhibited similar clinical features except normomagnesemia and bilateral kidney stones. The first younger brother of the proband harbored the same homozygous mutations in CLCNKB and exhibited clinical features of hypokalemia, normomagnesemia, hypercalciuria and hyperuricemia. Potassium chloride, spironolactone and potassium magnesium aspartate were prescribed to the proband to correct electrolytic disturbances. Benzbromarone and febuxostat were prescribed to correct hyperuricemia. The dose of potassium magnesium aspartate was subsequently increased to alleviate arthralgia resulting from calcium pyrophosphate deposition disease (CPPD). To the best of our knowledge, we are the first to report an exceptionally rare case in an inbred Chinese pedigree with simultaneous homozygous mutations in SLC12A3 and CLCNKB. GS and BS type III have significant intrafamilial phenotype heterogeneity. When arthralgia is developed in patients with GS and BS, gout and CPPD should both be considered. Full article

(This article belongs to the Special Issue Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis)

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Review

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17 pages, 993 KiB

Open AccessReview

Atherosclerosis in Different Vascular Locations Unbiasedly Approached with Mouse Genetics

by Yukako Kayashima and Nobuyo Maeda-Smithies

Genes 2020, 11(12), 1427; https://doi.org/10.3390/genes11121427 - 28 Nov 2020

Cited by 9 | Viewed by 3080

Abstract

Atherosclerosis in different vascular locations leads to distinct clinical consequences, such as ischemic stroke and myocardial infarction. Genome-wide association studies in humans revealed that genetic loci responsible for carotid plaque and coronary artery disease were not overlapping, suggesting that distinct genetic pathways might be involved for each location. While elevated plasma cholesterol is a common risk factor, plaque development in different vascular beds is influenced by hemodynamics and intrinsic vascular integrity. Despite the limitation of species differences, mouse models provide platforms for unbiased genetic approaches. Mouse strain differences also indicate that susceptibility to atherosclerosis varies, depending on vascular locations, and that the location specificity is genetically controlled. Quantitative trait loci analyses in mice suggested candidate genes, including Mertk and Stab2, although how each gene affects the location-specific atherosclerosis needs further elucidation. Another unbiased approach of single-cell transcriptome analyses revealed the presence of a small subpopulation of vascular smooth muscle cells (VSMCs), which are “hyper-responsive” to inflammatory stimuli. These cells are likely the previously-reported Sca1⁺ progenitor cells, which can differentiate into multiple lineages in plaques. Further spatiotemporal analyses of the progenitor cells are necessary, since their distribution pattern might be associated with the location-dependent plaque development. Full article

(This article belongs to the Special Issue Genetics and Genomics of Vascular, Glomerular Disorders and Thrombosis)

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