Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis
| Autor: | Zhengmao Hu, Jia-Da Li, Jing Liu, Runyi Tian, Jie Ling, Denise Yan, Qi Tian, Chufeng He, Jian Song, Lu Jiang, Hongsheng Chen, Meng Li, Susan H. Blanton, Yifang Yi, Yong Feng, Xuezhong Liu, Yalan Liu, Taoxi Li, Xinzhang Cai, Chang Liu, Ximan Li, Lingyun Mei, Hong Wu |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Proband China Heterozygote Adolescent Genotype Genetic Linkage Hearing loss Mutation Missense Deafness 030105 genetics & heredity Biology Genetic analysis Mice 03 medical and health sciences Genetic linkage Exome Sequencing medicine Animals Humans Missense mutation Exome Family Genetic Testing Hearing Loss Genetics (clinical) Exome sequencing Aged Genetics Wild type Sequence Analysis DNA Human genetics Cochlea Pedigree Mice Inbred C57BL Phenotype 030104 developmental biology Mutation Female Multidrug Resistance-Associated Proteins medicine.symptom |
| Zdroj: | Genetics in Medicine. 21:2744-2754 |
| ISSN: | 1098-3600 |
| Popis: | To determine the genetic etiology of deafness in a family (HN-SD01) with autosomal dominant nonsyndromic hearing loss (NSHL). Stepwise genetic analysis was performed on family HN-SD01, including hotspot variant screening, exome sequencing, virtual hearing loss gene panel, and genome-wide linkage analysis. Targeted region sequencing was used to screen ABCC1 in additional cases. Cochlear expression of Abcc1 was evaluated by messenger RNA (mRNA) and protein levels. Computational prediction, immunofluorescence, real-time quantitative polymerase chain reaction, and flow cytometry were conducted to uncover functional consequences of candidate variants. Stepwise genetic analysis identified a heterozygous missense variant, ABCC1:c.1769A>G (p.Asn590Ser), cosegregating with phenotype in HN-SD01. Screening of ABCC1 in an additional 217 cases identified candidate pathogenic variants c.692G>A (p.Gly231Asp) in a sporadic case and c.887A>T (p.Glu296Val) in a familial proband. Abcc1 expressed in stria vascularis and auditory nerve of mouse cochlea. Immunofluorescence showed p.Asn590Ser distributed in cytomembrane and cytoplasm, while wild type was shown only in cytomembrane. Besides, it generated unstable mRNA and decreased efflux capacity of ABCC1. Stepwise genetic analysis is efficient to analyze the genetic etiology of NSHL. Variants in ABCC1 are linked with NSHL and suggest an important role of extruding pumps in maintaining cochlea function. |
| Databáze: | OpenAIRE |
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