Structural basis for pathogenic variants of GJB2 and hearing levels of patients with hearing loss.
Connexin
GJB2
Gap junction
Genotype–phenotype correlation
Hereditary hearing loss
Molecular modeling
Journal
BMC research notes
ISSN: 1756-0500
Titre abrégé: BMC Res Notes
Pays: England
ID NLM: 101462768
Informations de publication
Date de publication:
10 May 2024
10 May 2024
Historique:
received:
15
08
2023
accepted:
30
04
2024
medline:
11
5
2024
pubmed:
11
5
2024
entrez:
10
5
2024
Statut:
epublish
Résumé
The crystal structure of the six protomers of gap junction protein beta 2 (GJB2) enables prediction of the effect(s) of an amino acid substitution, thereby facilitating investigation of molecular pathogenesis of missense variants of GJB2. This study mainly focused on R143W variant that causes hearing loss, and investigated the relationship between amino acid substitution and 3-D structural changes in GJB2. Patients with nonsyndromic hearing loss who appeared to have two GJB2 pathogenic variants, including the R143W variant, were investigated. Because the X-ray crystal structure of the six protomers of the GJB2 protein is known, R143W and structurally related variants of GJB2 were modeled using this crystal structure as a template. The wild-type crystal structure and the variant computer-aided model were observed and the differences in molecular interactions within the two were analyzed. The predicted structure demonstrated that the hydrogen bond between R143 and N206 was important for the stability of the protomer structure. From this prediction, R143W related N206S and N206T variants showed loss of the hydrogen bond. Investigation of the genotypes and clinical data in patients carrying the R143W variant on an allele indicated that severity of hearing loss depends largely on the levels of dysfunction of the pathogenic variant on the allele, whereas a patient with the homozygous R143W variant demonstrated profound hearing loss. We concluded that these hearing impairments may be due to destabilization of the protomer structure of GJB2 caused by the R143W variant.
Identifiants
pubmed: 38730444
doi: 10.1186/s13104-024-06793-w
pii: 10.1186/s13104-024-06793-w
doi:
Substances chimiques
Connexin 26
127120-53-0
GJB2 protein, human
0
Connexins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
131Subventions
Organisme : Japan Society for Promotion of Sciences
ID : 18K09365
Organisme : Japan Society for Promotion of Sciences
ID : 17K11350
Organisme : Grant-in-Aid for Clinical Research from the National Hospital Organization of Japan
ID : H30-NHO(kankakuki)-01
Informations de copyright
© 2024. The Author(s).
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