Dataset Information

Mutations in the ARAP3 Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes.

ABSTRACT: Background:ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the ARAP3 gene are associated with impaired lymphatic vessel formation. Objective:The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the ARAP3 gene in order to explore its role in the development of lymphedema. Methods and Results:We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including ARAP3. Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3. In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins. Conclusions:Based on our results, we propose that variants in ARAP3 could be included in genetic testing for lymphedema.

SUBMITTER: Ricci M

PROVIDER: S-EPMC7468673 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Mutations in the <i>ARAP3</i> Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes.

Ricci Maurizio M Compagna Rita R Amato Bruno B Kenanoglu Sercan S Veselenyiova Dominika D Kurti Danjela D Baglivo Mirko M Basha Syed Hussain SH Serrani Roberta R Miggiano Giacinto Abele Donato GAD Aquilanti Barbara B Matera Giuseppina G Marceddu Giuseppe G Velluti Valeria V Gagliardi Lucilla L Dundar Munis M Krajcovic Juraj J Bertelli Matteo M Bertelli Matteo M

International journal of genomics 20200825

<h4>Background</h4>ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the <i>ARAP3</i> gene are associated with impaired lymphatic vessel formation.<h4>Objective</h4>The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the <i>ARAP3</i> gene in order to explore its role in the development of lymphedema.<h4>Methods and resul ...[more]

PMID: 32908855

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Project description:To survey families with clinical evidence of autosomal dominant retinitis pigmentosa (adRP) for mutations in genes known to cause adRP.Two hundred adRP families, drawn from a cohort of more than 400 potential families, were selected by analysis of pedigrees. Minimum criteria for inclusion in the adRP cohort included either evidence of at least three generations of affected individuals or two generations with evidence of male-to-male transmission. Probands from each family were screened for mutations in 13 genes known to cause adRP: CA4, CRX, FSCN2, IMPDH1, NRL, PRPF3 (RP18), PRPF8 (RP13), PRPF31 (RP11), RDS, RHO, ROM1, RP1, and RP9. Families without mutations in autosomal genes and in which an X-linked mode of inheritance could not be excluded were tested for mutations in ORF 15 of X-linked RPGR. Potentially pathogenic variants were evaluated based on a variety of genetic and computational criteria, to confirm or exclude pathogenicity.A total of 82 distinct, rare (nonpolymorphic) variants were detected among the genes tested. Of these, 57 are clearly pathogenic based on multiple criteria, 10 are probably pathogenic, and 15 are probably benign. In the cohort of 200 families, 94 (47%) have one of the clearly pathogenic variants and 10 (5%) have one of the probably pathogenic variants. One family (0.5%) has digenic RDS-ROM1 mutations. Two families (1%) have a pathogenic RPGR mutation, indicating that families with apparent autosomal transmission of RP may actually have X-linked genetic disease. Thus, 107 families (53.5%) have mutations in known genes, leaving 93 whose underlying cause is still unknown.Together, the known adRP genes account for retinal disease in approximately half of the families in this survey, mostly Americans of European origin. Among the adRP genes, IMPDH1, PRPF8, PRPF31, RDS, RHO, and RP1 each accounts for more than 2% of the total; CRX, PRPF3, and RPGR each accounts for roughly 1%. Disease-causing mutations were not found in CA4, FSCN2, NRL, or RP9. Because some mutations are frequent and some regions are more likely to harbor mutations than others, more than two thirds of the detected mutations can be found by screening less than 10% of the total gene sequences. Among the remaining families, mutations may lie in regions of known genes that were not tested, mutations may not be detectable by PCR-based sequencing, or other loci may be involved.

Dataset Information

Mutations in the ARAP3 Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes.

Publications

Mutations in the <i>ARAP3</i> Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes.

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