Novel Mutations in the TMPRSS3 Gene may Contribute to Taiwanese Patients with Nonsyndromic Hearing Loss.

Swee-Hee Wong,Yung-Chang Yen,Shuan-Yow Li,Jiann-Jou Yang

doi:10.3390/ijms21072382

Abstract

A previous study indicated that mutations in the transmembrane protease serine 3 (TMPRSS3) gene, which encodes a transmembrane serine protease, cause nonsyndromic hearing loss (NSHL). This was the first description of a serine protease involved in hearing loss (HL). In Taiwan, however, data on the TMPRSS3 gene’s association with NSHL is still insufficient. In this study, we described 10 mutations of TMPRSS3 genes found in 14 patients after screening 230 children with NSHL. The prevalence of the TMPRSS3 mutation appeared to be 6.09% (14/230). Of the 10 mutations, three were missense mutations: c.239G>A (p.R80H), c.551T>C (p.L184S), and 1253C>T (p.A418V); three were silent mutations, and four were mutations in introns. To determine the functional importance of TMPRSS3 mutations, we constructed plasmids carrying TMPRSS3 mutations of p.R80H, p.L184S, and p.A418V. TMPRSS3 function can be examined by secretory genetic assay for site-specific proteolysis (sGASP) and Xenopus oocyte expression system. Our results showed that p.R80H, p.L184S, and p.A418V TMPRSS3 mutations gave ratios of 19.4%, 13.2%, and 27.6%, respectively, via the sGASP system. Moreover, these three TMPRSS3 mutations failed to activate the epithelial sodium channel (ENaC) in the Xenopus oocyte expression system. These results indicate that the p.R80H, p.L184S, and p.A418V missense mutations of TMPRSS3 resulted in greatly diminishing the proteolytic activity of TMPRSS3. Our study provides information for understanding the importance of TMPRSS3 in the NSHL of Taiwanese children and provides a novel molecular explanation for the role of TMPRSS3 in HL.

Highlights

Hearing loss (HL) is a common sensory disorder with an incidence of about 1 child in 1000 births in the human population [1]
Previous studies show that Transmembrane protease serine 3 (TMPRSS3) is a member of the TMPRSS family and causes autosomal recessive nonsyndromic hearing loss (ARNSHL) when its proteolytic ability is inactivated by 31 pathogenic mutations [7,12,13,15,20,21,22,23,24,25,26,27,28,29,30]
Our studies did not detect any of the aforementioned pathogenic variants and homozygous mutations in the TMPRSS3 gene, whereas we identified three novel heterozygous missense mutations, c

Summary

Introduction

Hearing loss (HL) is a common sensory disorder with an incidence of about 1 child in 1000 births in the human population [1]. The large C-terminal encompasses a stem region within the low density lipoprotein receptor class A (LDLRA) and scavenger receptor cysteine rich (SRCR) domains, a potential proteolytic activation cleavage site between p.R216 and p.I217, and a serine protease domain containing the catalytic triad signature (p.H257, p.D304, and p.S401). This structure suggests that TMPRSS3 could be active as a membrane-bound enzyme [8]

Objectives

Methods

Results

Conclusion