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

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

  • Genet Med. 2019 Dec;21(12):2744-2754. doi: 10.1038/s41436-019-0594-y.
Meng Li 1 2,  Lingyun Mei 1 2,  Chufeng He 1 2,  Hongsheng Chen 1 2,  Xinzhang Cai 1 2,  Yalan Liu 1 2,  Runyi Tian 3 4,  Qi Tian 3 4,  Jian Song 1 2,  Lu Jiang 1 2,  Chang Liu 1 2,  Hong Wu 1 2,  Taoxi Li 1 2 3,  Jing Liu 1 2,  Ximan Li 1,  Yifang Yi 1,  Denise Yan 5,  Susan H Blanton 5 6,  Zhengmao Hu 3 4,  Xuezhong Liu 1 5 6,  Jiada Li 3 4 7,  Jie Ling 8 9,  Yong Feng 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2 Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China.
  • 3 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • 4 Hunan Key Laboratory of Medical Genetics, Changsha, Hunan, China.
  • 5 Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 6 Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 7 Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan, China.
  • 8 Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China. lingjie@sklmg.edu.cn.
  • 9 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.
  • 10 Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan, China. fengyong_hn@hotmail.com.
  • 11 Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, Hunan, China. fengyong_hn@hotmail.com.
  • 12 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. fengyong_hn@hotmail.com.
  • 13 Hunan Jiahui Genetics Hospital, Changsha, Hunan, China. fengyong_hn@hotmail.com.
PMID: 31273342 DOI: 10.1038/s41436-019-0594-y
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.

Keywords

ABCC1; cochlea; extrusion pump; hearing loss; stepwise genetic analysis.

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