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A novel mutation in TRIOBP gene leading to congenital deafness in a Chinese family.

ABSTRACT: BACKGROUND:The autosomal recessive non-syndromic deafness DFNB28 is characterized by prelingual sensorineural hearing loss. The disease is related with mutations in TRIOBP (Trio- and F-actin-Binding Protein) gene, which has three transcripts referred to as TRIOBP-5, TRIOBP?-?4 and TRIOBP-1. Among them, TRIOBP-5/-?4 are expressed in the inner ears and crucial for maintaining the structure and function of the stereocilia. METHODS:The proband is a 26-year-old Chinese female. She and her younger brother have being suffered from severe deafness since birth, whereas her parents, who are cousins, have normal communication ability. Hearing impairment of the two siblings was determined by pure tone audiometry. Whole Exome Sequencing (WES) was performed on the genomic DNA of the proband and Sanger sequencing was conducted on the DNA samples of the four family members. RESULTS:Tests of pure tone hearing thresholds showed a severe to profound symmetric hearing loss for the proband and her younger brother. Moreover, a novel TRIOBP c.1342C?>?T (p.Arg448*) variant was identified by WES in the DNA sample of the proband and confirmed by Sanger sequencing in DNA of the family members. CONCLUSIONS:The TRIOBP c.1342C?>?T (p.Arg448*) variant is predicted to disrupt TRIOBP-5 and TRIOBP-4, which may lead to the congenital deafness. The results will broaden the spectrum of pathogenic variants in TRIOBP gene. The characteristics of deafness in the family imply that marriage between close relatives should be avoided.

SUBMITTER: Zhou B

PROVIDER: S-EPMC7268695 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A novel mutation in TRIOBP gene leading to congenital deafness in a Chinese family.

Zhou Bingxin B Yu Lili L Wang Yan Y Shang Wenjing W Xie Yi Y Wang Xiong X Han Fengchan F

BMC medical genetics 20200601 1

<h4>Background</h4>The autosomal recessive non-syndromic deafness DFNB28 is characterized by prelingual sensorineural hearing loss. The disease is related with mutations in TRIOBP (Trio- and F-actin-Binding Protein) gene, which has three transcripts referred to as TRIOBP-5, TRIOBP - 4 and TRIOBP-1. Among them, TRIOBP-5/- 4 are expressed in the inner ears and crucial for maintaining the structure and function of the stereocilia.<h4>Methods</h4>The proband is a 26-year-old Chinese female. She and ...[more]

PMID: 32487028

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Project description:BackgroundCongenital cataract is the leading cause of blindness in children worldwide. Approximately half of all congenital cataracts have a genetic basis. Protein aggregation is the single most important factor in cataract formation.MethodsA four-generation Chinese family diagnosed with autosomal dominant congenital cataracts and microphthalmia was recruited at the Shengjing Hospital of China Medical University. Genomic DNA was extracted from the peripheral blood of the participants. All coding exons and flanking regions of seven candidate genes (CRYAA, CRYBA4, CRYBB2, CRYGC, GJA8, MAF, and PITX3) were amplified and sequenced. Restriction fragment length polymorphism (RFLP) assays were performed to confirm the candidate causative variant, c.35G > T in the CRYAA gene. We constructed pcDNA3.1(+)-CRYAA expression plasmids containing either the wild-type or the R12L mutant alleles and respectively transfected them into HEK293T cells and into HeLa cells. Western blotting was performed to determine protein expression levels and protein solubility. Immunofluorescence was performed to determine protein sub-cellular localization.ResultsA heterozygous variant c.35G > T was identified in exon 1 of CRYAA, which resulted in a substitution of arginine to leucine at codon 12 (p.R12L). The nucleotide substitution c.35G > T was co-segregated with the disease phenotype in the family. The mutant R12L-CRYAA in HEK293T cells showed a significant increase in the expression level of the CRYAA protein compared with the wild-type cells. Moreover, a large amount of the mutant protein aggregated in the precipitate where the wild-type protein was not detected. Immunofluorescence studies showed that the overexpressed mutant CRYAA in HeLa cells formed large cytoplasmic aggregates and aggresomes.ConclusionsIn summary, we described a case of human congenital cataract and microphthalmia caused by a novel mutation in the CRYAA gene, which substituted an arginine at position 12 in the N-terminal region of αA-crystallin. The molecular mechanisms that underlie the pathogenesis of human congenital cataract may be characterized by the prominent effects of the p.R12L mutation on αA-crystallin aggregation and solubility. Our study also expands the spectrum of known CRYAA mutations.

Dataset Information

A novel mutation in TRIOBP gene leading to congenital deafness in a Chinese family.

Publications

A novel mutation in TRIOBP gene leading to congenital deafness in a Chinese family.

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