title: 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.
authors.affiliation: Department of Biotechnology, School of Basic Medical Science, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Biotechnology, School of Basic Medical Science, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Xuli
authors.initials: X
authors.lastname: Qian
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Jingxiao
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Biotechnology, School of Basic Medical Science, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Qinjun
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Biotechnology, School of Basic Medical Science, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Lu
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing, P.R. China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Biotechnology, School of Basic Medical Science, Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Otolaryngology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Guangqian
authors.initials: G
authors.lastname: Xing
mesh_terms: D000595:Amino Acid Sequence; D003062:Codon; D004252:DNA Mutational Analysis; D003638:Deafness / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment; D000076988:Sulfate Transporters
chemical_list: D003062:Codon; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters