Faculty Collaboration Database

Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis. Genet Med 2019 Dec;21(12):2744-2754

Date

07/06/2019

Pubmed ID

31273342

DOI

10.1038/s41436-019-0594-y

Scopus ID

2-s2.0-85068560679 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

PURPOSE: To determine the genetic etiology of deafness in a family (HN-SD01) with autosomal dominant nonsyndromic hearing loss (NSHL).

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Author List

Li M, Mei L, He C, Chen H, Cai X, Liu Y, Tian R, Tian Q, Song J, Jiang L, Liu C, Wu H, Li T, Liu J, Li X, Yi Y, Yan D, Blanton SH, Hu Z, Liu X, Li J, Ling J, Feng Y

Author

Ling Mei MD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Aged
Animals
China
Cochlea
Deafness
Exome
Family
Female
Genetic Linkage
Genetic Testing
Genotype
Hearing Loss
Heterozygote
Humans
Male
Mice
Mice, Inbred C57BL
Multidrug Resistance-Associated Proteins
Mutation
Mutation, Missense
Pedigree
Phenotype
Sequence Analysis, DNA