Two Novel Missense Mutations in the Connexin 26 Gene in Turkish Patients with Nonsyndromic Hearing Loss

Spectrum and Frequency of the GJB2 Gene Mutations Among Latvian Patients with Prelingual Nonsyndromic Hearing Loss Mutations in the GJB2 gene (connexin 26) are the most common cause of congenital nonsyndromic severe-to-profound hearing loss. Sixty-five hearing impaired probands from Latvia were tested for mutations in the GJB2 gene to determine the percentage of hearing loss attributed to connexin 26 and the types of mutations in this population. A total of 62% of patients tested had GJB2 mutations. Four different mutations in the GJB2 gene were identified in Latvian patients with nonsyndromic sensorineural hearing loss: 35delG, 311-324del14, 235delC and M34T. The most prevalent mutation is 35delG (47% of all probands were homozygous and 8% compound heterozygous). Our findings support the conclusion that the 35delG mutation is the most prevalent GJB2 mutation and that it is the common cause of hereditary nonsyndromic hearing loss in populations of European descent.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21072382 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2382

Author(s):

Swee-Hee Wong ◽

Yung-Chang Yen ◽

Shuan-Yow Li ◽

Jiann-Jou Yang

Keyword(s):

Hearing Loss ◽

Serine Protease ◽

Xenopus Oocyte ◽

Expression System ◽

Missense Mutations ◽

Nonsyndromic Hearing Loss ◽

Oocyte Expression ◽

Xenopus Oocyte Expression ◽

Oocyte Expression System ◽

Transmembrane Serine Protease

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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Screening of Connexin 26 in Nonsyndromic Hearing Loss

International Archives of Otorhinolaryngology ◽

10.1055/s-0034-1373783 ◽

2014 ◽

Vol 19 (01) ◽

pp. 030-033 ◽

Cited By ~ 4

Author(s):

Danielle Moreira ◽

Priscila Lopez ◽

Jair Mantovani ◽

Daniela Silva

Keyword(s):

Hearing Loss ◽

Connexin 26 ◽

Nonsyndromic Hearing Loss

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GJB2 mutations in Turkish patients with nonsyndromic hearing loss

Meta Gene ◽

10.1016/j.mgene.2016.10.006 ◽

2016 ◽

Vol 10 ◽

pp. 56-60

Author(s):

Nilnur Eyerci ◽

Enver Altaş ◽

İbrahim Pirim

Keyword(s):

Hearing Loss ◽

Nonsyndromic Hearing Loss ◽

Turkish Patients ◽

Gjb2 Mutations

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Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss

Physiological Genomics ◽

10.1152/physiolgenomics.00047.2009 ◽

2009 ◽

Vol 38 (3) ◽

pp. 281-290 ◽

Cited By ~ 46

Author(s):

Pu Dai ◽

Andrew K. Stewart ◽

Fouad Chebib ◽

Ann Hsu ◽

Julia Rozenfeld ◽

...

Keyword(s):

Hearing Loss ◽

Anion Exchange ◽

Diagnostic Yield ◽

Relative Rate ◽

Chinese Patients ◽

Missense Mutations ◽

Nonsyndromic Hearing Loss ◽

Direct Dna Sequencing ◽

Slc26a4 Gene ◽

The U.S

Mutations of the human SLC26A4/PDS gene constitute the most common cause of syndromic and nonsyndromic hearing loss. Definition of the SLC26A4 mutation spectrum among different populations with sensorineural hearing loss is important for development of optimal genetic screening services for congenital hearing impairment. We screened for SLC26A4 mutations among Chinese and U.S. subjects with hearing loss, using denaturing HPLC (DHPLC) and direct DNA sequencing. Fifty-two of 55 Chinese subjects with deafness accompanied by enlargement of the vestibular aqueduct (EVA) exhibited at least one mutant SLC26A4 allele, whereas SLC26A4 mutations were found in only 2 of 116 deaf Chinese patients without EVA. The spectrum of SLC26A4 mutations differed among Chinese and U.S. subjects and included 10 previously unreported SLC26A4 variants: 4 in the Chinese population (p.E303Q, p.X329, p.X467, p.X573) and 6 in the U.S. population (p.V250A, p.D266N, p.F354S, p.D697A, p.K715N, p.E737D). Among the seven novel in-frame missense mutations, five encoded SLC26A4 proteins with substantially reduced Cl−/anion exchange activity as expressed and measured in Xenopus oocytes, but four of these were sufficiently active to allow study of anion selectivity. The only mutant polypeptide exhibiting complete loss of anion exchange function, p.E303Q, was expressed at or near the oocyte surface at near-wild-type levels. Two variants, p.F354S and p.E737D, displayed selective reduction in relative rate of Cl−/HCO3− exchange compared with similarly measured rates of Cl−/Cl− and Cl−/I− exchange. Our data show that mutation analysis of the SLC26A4 gene is of high diagnostic yield among subjects with deafness and bilateral EVA in both China and the U.S. However, the pathogenicity of monoallelic SLC26A4 gene variants in patients with hearing loss remains unclear in many instances.

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Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss

Clinical Genetics ◽

10.1111/j.1399-0004.2005.00468.x ◽

2005 ◽

Vol 68 (2) ◽

pp. 161-166 ◽

Cited By ~ 29

Author(s):

V Piazza ◽

M Beltramello ◽

M Menniti ◽

E Colao ◽

P Malatesta ◽

...

Keyword(s):

Functional Analysis ◽

Hearing Loss ◽

Connexin 26 ◽

Nonsyndromic Hearing Loss ◽

Gene Coding

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The Functional Role of CONNEXIN 26 Mutation in Nonsyndromic Hearing Loss, Demonstrated by Zebrafish Connexin 30.3 Homologue Model

Cells ◽

10.3390/cells9051291 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1291

Author(s):

Hsuan-An Su ◽

Ting-Wei Lai ◽

Shuan-Yow Li ◽

Tzu-Rong Su ◽

Jiann-Jou Yang ◽

...

Keyword(s):

Hearing Loss ◽

Structural Changes ◽

Dominant Negative ◽

Gjb2 Gene ◽

Dominant Negative Effect ◽

Connexin 26 ◽

Transgenic Zebrafish ◽

Nonsyndromic Hearing Loss ◽

Transgenic Lines

Nonsyndromic hearing loss (NSHL) is of great clinical importance, and mutations in the GJB2 gene and the encoded human CONNEXIN 26 (CX26) protein play important roles in the genetic pathogenesis. The CX26 p.R184Q mutation was shown to be a dominant-negative effect in our previous study. Previously, we also demonstrated that zebrafish Cx30.3 is orthologous to human CX26. In the present study, we established transgenic zebrafish models with mutated Cx30.3 specifically expressed in the supporting cells of zebrafish inner ears driven by the agr2 promoter, to demonstrate and understand the mechanism by which the human CX26 R.184 mutation causes NSHL. Our results indicated that significant structural changes in the inner ears of transgenic lines with mutations were measured and compared to wild-type zebrafish. Simultaneously, significant alterations of transgenic lines with mutations in swimming behavior were analyzed with the zebrafish behavioral assay. This is the first study to investigate the functional results of the CX26 p.R184Q mutation with in vivo disease models. Our work supports and confirms the pathogenic role of the CX26 p.R184Q mutation in NSHL, with a hypothesized mechanism of altered interaction among amino acids in the connexins.

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