Understanding of the molecular evolution of deafness-associated pathogenic mutations of connexin 26
| Autor: | Qinjun Wei, Guangqian Xing, Xin Cao, Yi Fan, Xin-Huan Han |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Hearing Loss
Sensorineural DNA Mutational Analysis Molecular Sequence Data Mutation Missense Connexin Plant Science Biology medicine.disease_cause Connexins Protein Structure Secondary Evolution Molecular Protein structure Molecular evolution Phylogenetics otorhinolaryngologic diseases Genetics medicine Animals Humans Missense mutation Amino Acid Sequence Gene Peptide sequence Phylogeny Mutation Bayes Theorem General Medicine Protein Structure Tertiary Connexin 26 Insect Science Animal Science and Zoology |
| Zdroj: | Genetica. 142:555-562 |
| ISSN: | 1573-6857 0016-6707 |
| Popis: | Connexins (Cxs) were first identified as subunit proteins of the intercellular membrane channels that cluster in the cell communication structures known as gap junctions. Mutations in the gap junction β2 (GJB2) gene encoding connexin 26 (Cx26) have been linked to sporadic and hereditary hearing loss. In some cases, the mechanisms through which these mutations lead to hearing loss have been partly elucidated using cell culture systems and animal models. The goal of this study was to re-assess the pathogenic roles of the GJB2 mutations by combining comparative evolutionary studies. We used Bayesian phylogenetic analyses to determine the relationships among 35 orthologs and to calculate the ancestral sequences of these orthologs. By aligning sequences from the 35 orthologs and their ancestors and categorizing amino acid sites by degree of conservation, we used comparative evolutionary methods to determine potential functionally important amino acid sites in Cx26 and to identify missense changes that are likely to affect function. We identified six conserved regions in Cx26, five of which are located in the Connexin_CCC, and another is in the connexin super family domain. Finally, we identified 51 missense changes that are likely to disrupt function, and the probability of these changes occurring at hydrophilic amino acid residues was twice that of occurring at hydrophobic residues in the trans-membrane regions of Cx26. Our findings, which were obtained by combining comparative evolutionary methods to predict Cx26 mutant function, are consistent with the pathogenic characteristics of Cx26 mutants. This study provides a new pathway for studying the role of aberrant Cx26 in hereditary hearing loss. |
| Databáze: | OpenAIRE |
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