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, Xue Z Liu & 3 others Jiada Li, Jie Ling, Yong Feng

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StatePublished - Jan 1 2019

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Cochlea
Medical Genetics
Fluorescent Antibody Technique
Stria Vascularis
Exome
Cochlear Nerve
Messenger RNA
Deafness
Hearing Loss
Real-Time Polymerase Chain Reaction
Flow Cytometry
Cytoplasm
Genome
Phenotype
Genes
Nonsyndromic Deafness
Proteins

Keywords

  • ABCC1
  • cochlea
  • extrusion pump
  • hearing loss
  • stepwise genetic analysis

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis. / Li, Meng; Mei, Lingyun; He, Chufeng; Chen, Hongsheng; Cai, Xinzhang; Liu, Yalan; Tian, Runyi; Tian, Qi; Song, Jian; Jiang, Lu; Liu, Chang; Wu, Hong; Li, Taoxi; Liu, Jing; Li, Ximan; Yi, Yifang; Yan, Denise; Blanton, Susan H; Hu, Zhengmao; Liu, Xue Z; Li, Jiada; Ling, Jie; Feng, Yong.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

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, XZ, Li, J, Ling, J & Feng, Y 2019, 'Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis', Genetics in Medicine. https://doi.org/10.1038/s41436-019-0594-y
Li, Meng ; Mei, Lingyun ; He, Chufeng ; Chen, Hongsheng ; Cai, Xinzhang ; Liu, Yalan ; Tian, Runyi ; Tian, Qi ; Song, Jian ; Jiang, Lu ; Liu, Chang ; Wu, Hong ; Li, Taoxi ; Liu, Jing ; Li, Ximan ; Yi, Yifang ; Yan, Denise ; Blanton, Susan H ; Hu, Zhengmao ; Liu, Xue Z ; Li, Jiada ; Ling, Jie ; Feng, Yong. / Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis. In: Genetics in Medicine. 2019.
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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.",
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T1 - Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis

AU - Li, Meng

AU - Mei, Lingyun

AU - He, Chufeng

AU - Chen, Hongsheng

AU - Cai, Xinzhang

AU - Liu, Yalan

AU - Tian, Runyi

AU - Tian, Qi

AU - Song, Jian

AU - Jiang, Lu

AU - Liu, Chang

AU - Wu, Hong

AU - Li, Taoxi

AU - Liu, Jing

AU - Li, Ximan

AU - Yi, Yifang

AU - Yan, Denise

AU - Blanton, Susan H

AU - Hu, Zhengmao

AU - Liu, Xue Z

AU - Li, Jiada

AU - Ling, Jie

AU - Feng, Yong

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - ABCC1

KW - cochlea

KW - extrusion pump

KW - hearing loss

KW - stepwise genetic analysis

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