Probing the Effect of Two Heterozygous Mutations in Codon 723 of SLC26A4 on Deafness Phenotype Based on Molecular Dynamics Simulations

Abstract

A Chinese family was identified with clinical features of enlarged vestibular aqueduct syndrome (EVAS). The mutational analysis showed that the proband (III-2) had EVAS with bilateral sensorineural hearing loss and carried a rare compound heterozygous mutation of SLC26A4 (IVS7-2A>G, c.2167C>G), which was inherited from the same mutant alleles of IVS7-2A>G heterozygous father and c.2167C>G heterozygous mother. Compared with another confirmed pathogenic biallelic mutation in SLC26A4 (IVS7-2A>G, c.2168A>G), these two biallelic mutations shared one common mutant allele and the same codon of the other mutant allele, but led to different changes of amino acid (p.H723D, p.H723R) and both resulted in the deafness phenotype. Structure-modeling indicated that these two mutant alleles changed the shape of pendrin protein encoded by SLC26A4 with increasing randomness in conformation, and might impair pendrin’s ability as an anion transporter. The molecular dynamics simulations also revealed that the stability of mutant pendrins was reduced with increased flexibility of backbone atoms, which was consistent with the structure-modeling results. These evidences indicated that codon 723 was a hot-spot region in SLC26A4 with a significant impact on the structure and function of pendrin, and acted as one of the genetic factors responsible for the development of hearing loss.

A novel compound heterozygous mutation of SLC26A4 in two Chinese families with nonsyndromic hearing loss and enlarged vestibular aqueducts

“…It has been reported that the mutant pendrin comprised p.H723R is localized predominantly in endoplasmic reticulum and was found to lack the activity of anion exchange (18). It was also found that patients with two bi-allelic mutations of p.H723R or a compound heterozygous mutation with the other mutation often suffered from bilateral SHL (19)(20)(21). The other mutant allele c.1644_1645insA mutation of SLC26A4 was identified as a novel compound heterozygous mutation with p.H723R in the present study.…”

Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA

“…Several studies have investigated the genotype–phenotype correlation of deafness with SLC26A4 mutations. 35 – 40 Tsukamoto et al 26 reported that 78.13% (25/32) of EVA-positive patients carried SLC26A4 mutations in the Japanese population, while 46.94% (23/49) of such patients carried mutations in the Chinese population. 11 Additionally, we found that the overall mutations in the SLC26A4 gene accounted for 73.64% (648/880) of the patients with EVA.…”