ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment

Thashi Bharadwaj,Zubair M Ahmed,Ghazanfar Ali,Sakina Rehman,Regie Lyn P Santos‐Cortez ,Liz M Nouel-Saied ,Brian M Mcdermott,Jenna L Everard ,Arnaud P J Giese,Michael J Bamshad,Anushree Acharya,Saima Riazuddin,Abdul Nasır ,Wasim Ahmad,Lana M Pollock,Shaoyuan Zhu,Deborah A Nickerson,Raheel Ali ,Khurram Liaqat,Suzanne M Leal,Asmat Ullah,Muhammad Ansar,Abdul Wali,Isabelle Schrauwen

doi:10.1038/s41431-021-00913-x

Abstract

Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.

Highlights

Hearing impairment (HI) is a highly heterogeneous and common sensory disorder [1]
Of the rare ARNSHI variants that were identified (Supplementary Table 1) through exome sequencing only four homozygous variants in ADAMTS1 (NM_006988.5) [c.403T>G:p.(Ser135Ala)] family 4457; MPDZ (NM_003829.4) [c.2324C>T:p.(Pro775Leu)] family 4876; MVD (NM_002461.3) [c.1136C>A:p.(Pro379His)] family 4140; and SEZ6 (NM_178860.5) [c.2092G>A:p. (Val698Ile)] family 4444 segregated with HI (Fig. 1A, Table 1 and Supplementary Table 2)
We identified candidate HI genes, ADAMTS1, MPDZ, MVD, and SEZ6, via exome sequencing of DNA samples obtained from four consanguineous Pakistani families that segregate ARNSHI

Summary

Introduction

Hearing impairment (HI) is a highly heterogeneous and common sensory disorder [1]. The prevalence of congenital HI is estimated to be 1 in 500 newborns [2]. To date >80 genes have been implicated in autosomal recessive (AR) nonsyndromic HI (NSHI). Close to a third of ARNSHI genes have been identified via the study of large Pakistani consanguineous families [2]. We identified homozygous missense variants in candidate genes: ADAMTS1 (OMIM: 605174); MPDZ (OMIM: 603785); MVD (OMIM: 603236); and SEZ6 (OMIM: 616666), which are likely to be the underlying cause of AR sensorineural profound NSHI in four consanguineous Pakistani families. These candidate genes were identified and studied using a combination of technologies that included Sanger and exome sequencing, linkage analysis, and expression studies

Methods

Results

Conclusion