Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis

Meng Li; Lingyun Mei; Chufeng He; Hongsheng Chen; Xinzhang Cai; Yalan Liu; Runyi Tian; Qi Tian; Jian Song; Lu Jiang; Chang Liu; Hong Wu; Taoxi Li; Jing Liu; Ximan Li; Yifang Yi; Denise Yan; Susan H Blanton; Zhengmao Hu; Xuezhong Liu; Jiada Li; Jie Ling; Yong Feng

doi:10.1038/s41436-019-0594-y

Back

Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis

Journal article

Peer reviewed

Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis

Meng Li, Lingyun Mei, Chufeng He, Hongsheng Chen, Xinzhang Cai, Yalan Liu, Runyi Tian, Qi Tian, Jian Song, Lu Jiang, …

Genetics in medicine, Vol.21(12), pp.2744-2754

2019-12

DOI: https://doi.org/10.1038/s41436-019-0594-y

PMID: 31273342

Abstract

Deafness - genetics

Genetic Testing

Humans

Male

Mutation, Missense

Exome

Cochlea - metabolism

China

Adult

Female

Multidrug Resistance-Associated Proteins - genetics

Genetic Linkage

Mice, Inbred C57BL

Genotype

Deafness - etiology

Whole Exome Sequencing

Hearing Loss - genetics

Phenotype

Animals

Deafness - metabolism

Pedigree

Adolescent

Family

Heterozygote

Aged

Mice

Mutation

Multidrug Resistance-Associated Proteins - metabolism

Sequence Analysis, DNA - methods

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.

Metrics

9 Record Views

13 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.219 Cancer Drugs; 1.219.638 P-Glycoprotein
Web Of Science research areas: Genetics & Heredity
ESI research areas: Clinical Medicine

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis
Creators: Meng Li - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Lingyun Mei - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Chufeng He - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Hongsheng Chen - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Xinzhang Cai - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Yalan Liu - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Runyi Tian - Hunan Key Laboratory of Medical Genetics, Changsha, Hunan, China
Qi Tian - Hunan Key Laboratory of Medical Genetics, Changsha, Hunan, China
Jian Song - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Lu Jiang - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Chang Liu - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Hong Wu - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Taoxi Li - Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
Jing Liu - Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China
Ximan Li - Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China
Yifang Yi - Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China
Denise Yan - Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA
Susan H Blanton - Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
Zhengmao Hu - Hunan Key Laboratory of Medical Genetics, Changsha, Hunan, China
Xuezhong Liu - Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
Jiada Li - Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan, China
Jie Ling - Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University and Hunan Key Laboratory of Molecular Precision Medicine, Changsha, Hunan, China. lingjie@sklmg.edu.cn
Yong Feng - Hunan Jiahui Genetics Hospital, Changsha, Hunan, China. fengyong_hn@hotmail.com
Publication Details: Genetics in medicine, Vol.21(12), pp.2744-2754
Publisher: United States
Grant note: R01 DC012115 / NIDCD NIH HHS R01 DC005575 / NIDCD NIH HHS
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Department of Otolaryngology; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 31273342
Record Identifier: 991031576701202976