Identification ofTMPRSS3as a Significant Contributor to Autosomal Recessive Hearing Loss in the Chinese Population

Abstract

Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Mutations in the TMPRSS3 (transmembrane protease, serine 3) gene cause prelingual (DFNB10) or postlingual (DFNB8) deafness. In our previous study, three pathogenic mutations in TMPRSS3 were identified in one Chinese family. To evaluate the importance of TMPRSS3 mutations in recessive deafness among the Chinese, we screened 150 autosomal recessive nonsyndromic hearing loss (ARNSHL) families and identified 6 that carried seven causative TMPRSS3 mutations, including five novel mutations (c.809T>A, c.1151T>G, c.1204G>A, c.1244T>C, and c.1250G>A) and two previously reported mutations (c.323-6G>A and c.916G>A). Each of the five novel mutations was classified as severe, by both age of onset and severity of hearing loss. Together with our previous study, six families were found to share one pathogenic mutation (c.916G>A, p.Ala306Thr). To determine whether this mutation arose from a common ancestor, we analyzed six short tandem repeat (STR) markers spanning the TMPRSS3 gene. In four families, we observed linkage disequilibrium between p.Ala306Thr and STR markers. Our results indicate that mutations in TMPRSS3 account for about 4.6% (7/151) of Chinese ARNSHL cases lacking mutations in SLC26A4 or GJB2 and that the recurrent TMPRSS3 mutation p.Ala306Thr is likely to be a founder mutation.

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

“…All previous studies indicate that a recessive mutation form in the TMPRSS3 gene is associated with NSHL [12]. Nevertheless, we only found heterozygous mutations forming in the TMPRSS3 gene and a low incidence rate in Taiwanese patients with NSHL.…”

“…TMPRSSs, which are involved in various physiological and pathological processes, are an emerging class of proteolytic enzyme [18,19]. Previous studies show that 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]. In contrast, 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.239 G>A (p.R80H), c.551 T>C (p.L184S), and c.1253 C>T (p.A418V), in patients with NSHL.…”

“…A study on TMPRSS3 was the first to report that an enzyme can be associated with NSHL and that it can be related to maintaining Na + within the endolymphatic environment in the cochlea [9,10]. To date, 31 different TMPRSS3 mutations that lie in all functional domains have been described and have been reported to disrupt the proteolytic activity of TMPRSS3 in more than 14 ethnic groups worldwide, including Asian, Mediterranean, and Caucasian populations [11][12][13]. However, in Taiwan, data on the TMPRSS3 gene associated with NSHL are still insufficient.…”

The Analysis of A Frequent TMPRSS3 Allele Containing P.V116M and P.V291L in A Cis Configuration among Deaf Koreans

“…We initially hypothesized that p.V116M in the SRCR domain alone or in conjunction with p.V291L in the serine protease domain would significantly destroy the function of the allele, based on the data available in the literature. According to the literature, detection frequency of pathogenic variants in the serine protease, SRCR, LDL receptor like domain and transmembrane domains of this gene has been recently reported to be 0.41(16/39), 0.33 (13/39), 0.20 (8/39), and 0.05 (2/39), respectively [ 15 ]. Although Lee et al (2003) predicted that mutations in the SRCR and LDLRA domains affect the proper folding or assembly of the catalytic domain or alter protease substrate recognition and binding [ 16 ], however, there has not been any established domain-phenotype correlation in this gene.…”

Identification of a complex genomic rearrangement in TMPRSS3 by massively parallel sequencing in Chinese cases with prelingual hearing loss

“…Approximately 60% of HL is caused by genetic factors (Morton & Nance, ). Nonsyndromic hearing loss (NSHL), in which hearing impairment is the only obvious clinical abnormality, accounts for 70% of the genetic cases (Gao et al, ). Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common type in NSHL, usually manifested as severe to profound, prelingual and nonprogressive HL (Petersen & Willems, ).…”