Novel Mutations and Mutation Combinations of<i>TMPRSS3</i>Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

Gao, Xue; Yuan, Yongyi; Wang, Guojian; Xu, Jin; Su, Yu; Lin, Xiaobo; Dai, Pu

doi:10.1155/2017/4707315

Cited by 15 publications

(22 citation statements)

References 26 publications

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“…Conversely, it is possible that more pathogenic CLRN2 mutations may elicit a more severe, early‐onset hearing loss phenotype. There are examples of this, for instance TMPRSS3 , encoding transmembrane protease serine 3, has been reported to cause severe‐to‐profound prelingual hearing loss (DFNB10) as well as progressive hearing impairment with post‐lingual onset (DFNB8) due to differential pathogenic mutations (Gao et al , ). Of note, a recent work by Gopal S. and colleagues reported a recessively inherited non‐syndromic sensorineural hearing loss in a consanguineous Iranian family caused by a CLRN2 mutation that results in a missense mutation in the encoded protein (Gopal et al , ).…”

Section: Discussionmentioning

confidence: 99%

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

et al. 2019

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Hearing relies on mechanically gated ion channels present in the actin‐rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound‐receptive structure is limited. Utilizing a large‐scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early‐onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non‐syndromic progressive hearing loss. Our in‐depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin‐2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin‐2 leads to loss of mechano‐electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin‐2 in mammalian hearing, providing insights into the interplay between mechano‐electrical transduction and stereocilia maintenance.

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Section: Discussionmentioning

confidence: 99%

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

et al. 2019

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“…In deafness pedigrees, variants affecting protein function in 12 genes were verified with the positive diagnostic rate 56.67% (17/30) ( Table 3). Detailed information on these deafness pedigrees is provided in our previous studies [22][23][24][25][26][27][28][29].…”

Section: Positive Diagnostic Rate For Snvsmentioning

confidence: 99%

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

Yuan

et al. 2019

Eur J Hum Genet

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Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wong

Yen

et al. 2020

IJMS

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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.

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Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

Cited by 15 publications

References 26 publications

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls

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

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