Functional consequences of Genetics variant in TMC1 and TMC2 within a United Arab Emirates family with Pre-lingual hearing loss

Abdullah Al Mutery; Walaa Kamal Eldin Mohamed; Mona Mahfood; Jihen Chouchen; Abdelaziz Tlili

doi:10.1016/j.sjbs.2022.103520

Functional consequences of Genetics variant in TMC1 and TMC2 within a United Arab Emirates family with Pre-lingual hearing loss

Saudi J Biol Sci. 2023 Feb;30(2):103520. doi: 10.1016/j.sjbs.2022.103520. Epub 2022 Dec 1.

Authors

Abdullah Al Mutery^{1

2

3}, Walaa Kamal Eldin Mohamed^{1

4}, Mona Mahfood¹, Jihen Chouchen³, Abdelaziz Tlili^{1

2

3}

Affiliations

¹ Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates.
² Human Genetics & Stem Cells Research Group, Research Institute of Sciences & Engineering, University of Sharjah, Sharjah, United Arab Emirates.
³ Molecular Genetics and Stem Cell Research Laboratory, University of Sharjah, Sharjah, United Arab Emirates.
⁴ Department de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Barcelona, Spain.

Abstract

Hearing loss (HL) is the most prevalent sensory disorder whose etiology comes from environmental and/or genetic factors. Approximately 60 % of HL cases are due to mutations in genes responsible for maintaining a normal hearing function. Despite the monogenic inheritance of hereditary hearing loss (HHL), its diagnosis is challenging as both clinical and genetic heterogeneity characterizes it. Through the development of next-generation sequencing (NGS) techniques, the number of identified mutations responsible for HHL has increased exponentially during the last decade. Mutations in the TMC1 have been reported in several patients with nonsyndromic hereditary hearing loss (NSHHL), more precisely in cases with an autosomal recessive inheritance pattern. In this study, we conducted whole-exome sequencing (WES) analysis of a United Arabs Emirates (UAE) family with autosomal recessive nonsyndromic hearing loss (ARNSHL). This analysis revealed segregation of the TMC1 missense mutation c.596A > T (p.Asn199Ile) with the disease. Bioinformatics analysis supported the pathogenic effect of this mutation and predicted its impact at the proteomics level. Molecular docking analysis of TMC2WT, TMC2R123K, TMC2Q205R, and TMC2R123K + Q205R. Finally, protein docking results suggest a role for TMC2 variants in the phenotypic variability observed within the investigated family.

Keywords: ARNSHL, Autosomal Recessive Nonsyndromic Hearing Loss; GATK, Genome Analysis Toolkit; GnomAD, Genome Aggregation Database; HHL, Hereditary Hearing Loss; HL, Hearing Loss; NGS, Next Generation Sequencing; NSHHL, Nonsyndromic Hereditary Hearing Loss; Non-syndromic Hearing Loss; PCR, Polymerase Chain Reaction; Phenotypic variability; Protein docking; TMC1; UAE, United Arabs Emirates; WES, Whole-Exome Sequencing; Whole-exome sequencing; c.596A > T mutation.