A non-coding variant in 5' untranslated region drove up-regulation of pseudo-kinase EPHA10 and caused non-syndromic hearing loss in humans

Sida Huang; Lu Ma; Xuezhong Liu; Chufeng He; Jiada Li; Zhengmao Hu; Lu Jiang; Yalan Liu; Xianlin Liu; Yong Feng; Xinzhang Cai

doi:10.1093/hmg/ddac223

A non-coding variant in 5' untranslated region drove up-regulation of pseudo-kinase EPHA10 and caused non-syndromic hearing loss in humans

Hum Mol Genet. 2023 Feb 19;32(5):720-731. doi: 10.1093/hmg/ddac223.

Authors

Sida Huang^{1

2

3}, Lu Ma^{4

5}, Xuezhong Liu^{6

7}, Chufeng He^{1

2

3}, Jiada Li⁸, Zhengmao Hu⁸, Lu Jiang^{1

2

3}, Yalan Liu^{1

2

3}, Xianlin Liu^{1

2

3}, Yong Feng^{1

4

9}, Xinzhang Cai^{1

2

3}

Affiliations

¹ Department of Otorhinolaryngology, Xiangya Hospital Central South University, Changsha, Hunan 410008, People's Republic of China.
² Key Laboratory of Otolaryngology Major Disease Research of Hunan Province, Changsha, Hunan 410008, People's Republic of China.
³ National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
⁴ Institute of Otorhinolaryngology, Head and Neck Surgery, University of South China, Changsha, Hunan 410004, People's Republic of China.
⁵ The Hengyang Key Laboratory of Cellular Stress Biology, Institute of Cytology and Genetics, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, People's Republic of China.
⁶ Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
⁷ Dr. John T. Macdonald Foundation Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
⁸ Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, People's Republic of China.
⁹ Department of Otorhinolaryngology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan 410008, People's Republic of China.

PMID: 36048850
DOI: 10.1093/hmg/ddac223

Abstract

Hereditary hearing loss has a genetic and phenotypic heterogeneity. However, it is still difficult to explain this heterogeneity perfectly with known deafness genes. Here, we report a novel causative gene EPHA10 as well as its non-coding variant in 5' untranslated region identified in a family with post-lingual autosomal dominant non-syndromic hearing loss from southern China. One affected member of this family had an ideal hearing restoration after cochlear implantation. We speculated that there were probable deafness-causing abnormalities in the cochlea according to clinical imaging and auditory evaluations. A heterozygous variant c.-81_-73delinsAGC was found co-segregating with hearing loss. Epha10 was expressed in mouse cochlea at both transcription and translation levels. The variant caused upregulation of EPHA10 which may result from promoter activity enhancement after sequence change. Overexpression of Eph (the homolog of human EPHA10) exerted effects on the structure and function of chordotonal organ in fly model. In summary, our study linked pseudo-kinase EPHA10 to hearing loss in humans for the first time.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5' Untranslated Regions
Animals
Deafness* / genetics
Hearing Loss* / genetics
Hearing Loss, Sensorineural* / genetics
Humans
Mice
Mutation
Pedigree
Receptors, Eph Family / genetics
Up-Regulation

Substances

5' Untranslated Regions
EPHA10 protein, human
Receptors, Eph Family

Supplementary concepts

Nonsyndromic Deafness