TMPRSS3 mutations in autosomal recessive nonsyndromic hearing loss

Battelino, Saba; Klančar, Gašper; Kovač, Jernej; Battelino, Tadej; Podkrajšek, Katarina Trebušak

doi:10.1007/s00405-015-3671-0

Cited by 26 publications

(23 citation statements)

References 17 publications

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“…For example, the 18 genes we flag in the context of echolocation, have all been observed to cause cochlear ganglion degeneration when mutated. As expected, several of these genes have also been implicated in human hearing loss 30,31 . A nice amino acid level example of "right" and "wrong" mutations (in the right context, at the right time) is the convergent bat & whale F115Y mutation in GJB2, found at the center of three codons, each of which is known to independently cause hearing loss in humans when mutated 32 (Fig.…”

Section: Discussionsupporting

confidence: 77%

A novel unbiased test for molecular convergent evolution and discoveries in echolocating, aquatic and high-altitude mammals

Marcovitz

Turakhia

Gloudemans

et al. 2017

Preprint

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Distantly related species entering similar biological niches often adapt by evolving similar morphological and physiological characters. The extent to which genomic molecular convergence, and the extent to which coding mutations underlie this convergent phenotypic evolution remain unknown. Using a novel test, we ask which group of functionally coherent genes is most affected by convergent amino acid substitutions between phenotypically convergent lineages. This most affected sets reveals 75 novel coding convergences in important genes that pattern a highly adapted organ: the cochlea, skin and lung in echolocating, aquatic and high-altitude mammals, respectively. Our test explicitly requires the enriched converged term to not be simultaneously enriched for divergent mutations, and correctly dismisses relaxation-based signals, such as those produced by vision genes in subterranean mammals. This novel test can be readily applied to birds, fish, flies, worms etc., to discover more of the fascinating contribution of protein coding convergence to phenotype convergence.

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Section: Discussionsupporting

confidence: 77%

A novel unbiased test for molecular convergent evolution and discoveries in echolocating, aquatic and high-altitude mammals

Marcovitz

Turakhia

Gloudemans

et al. 2017

Preprint

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“…The genetic load of TMPRSS3 in ARNSHL varies with ethnicity but is commonly a responsible gene in several populations. The frequency of TMPRSS3 mutations in childhood ARNSHL cases was 12% (3/25) in Turkish families negative for GJB2 mutations [5]; 13.1% (5/38) in Slovenian ARNSHL patients negative for GJB2 , GJB6 , and mitochondrial A1555G mutations [6]; and 0.45% (2/448) in a European population with childhood deafness negative for the GJB2 35delG mutation [7]. The frequency is approximately 1.8% (8/449) in the Pakistani population [8], 5% (2/39) in Tunisian families affected by profound ARNSHL [9], 2.5% (1/40) in a Korean ARNSHL study [10], and 5.9% (3/51) in a Korean ARNSHL population negative for the GJB2 mutation [11].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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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%

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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TMPRSS3 mutations in autosomal recessive nonsyndromic hearing loss

Cited by 26 publications

References 17 publications

A novel unbiased test for molecular convergent evolution and discoveries in echolocating, aquatic and high-altitude mammals

A novel unbiased test for molecular convergent evolution and discoveries in echolocating, aquatic and high-altitude mammals

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

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

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