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Cited by 3Hearing, Cochlea, Tinnitus, GeneticsConnexins and lens biologyHearing Loss and Rehabilitation

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.

Structural basis for pathogenic variants of GJB2 and hearing levels of patients with hearing loss

Open access
Namba, Kazunori, Mutai, Hideki, Matsunaga, Tatsuo, Kaneko, Hiroki·2024·BMC Research Notes
DOI 10.1186/s13104-024-06793-wPMC PMC11083831

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Abstract

Objectives: 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. Methods: 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. Results: 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. Conclusion: 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.

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Figures

Fig. 1. 3-D structures of the wild-type and variants of GJB2. a The hemichannel crystal structure consisting of six wild-type GJB2 proteins. The positions R143 and N206 in one of the GJB2 hexamers are indicated by yellow circles. b Hydrogen bond between R143 on helix 3 and N206 on helix 4 of wild-type proteins is indicated in red. c–e The hydrogen bond was absent in R143W (c), N206T (d), and N206S (e) variants. Arrows indicate the position of the hydrogen bonds
Fig. 1. 3-D structures of the wild-type and variants of GJB2. a The hemichannel crystal structure consisting of six wild-type GJB2 proteins. The positions R143 and N206 in one of the GJB2 hexamers are indicated by yellow circles. b Hydrogen bond between R143 on helix 3 and N206 on helix 4 of wild-type proteins is indicated in red. c–e The hydrogen bond was absent in R143W (c), N206T (d), and N206S (e) variants. Arrows indicate the position of the hydrogen bondsCC BY · PubMed Central
Fig. 2 Hearing levels of patients carrying p.R143W variant of GJB2. Hearing levels of 22 patients with each genotype, including at least one R143W variant, were shown. See [18] for the classification of the hearing levels
Fig. 2 Hearing levels of patients carrying p.R143W variant of GJB2. Hearing levels of 22 patients with each genotype, including at least one R143W variant, were shown. See [18] for the classification of the hearing levelsCC BY · PubMed Central

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Metadata

Authors
Namba, K., Mutai, H., Matsunaga, T., & Kaneko, H.
Affiliations
  • Tokyo Medical Center (JP)
  • Nihon University (JP)
Corresponding author
Kaneko, Hiroki
ORCID
Venue
BMC Research Notes
Publisher
Springer Science and Business Media LLC
Published
2024-05-10
Volume
17
Issue
1
Pages
131-131
ISSN
1756-0500 (ISSN-L)
DOI
10.1186/s13104-024-06793-w
PMC
PMC11083831
OpenAlex
W4396808728
Cited by
3
References
40
Citations by year
2026: 1 · 2025: 2
FWCI
0.84
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Research Notes (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Society for Promotion of Sciences (18K09365, 17K11350)
  • Grant-in-Aid for Clinical Research from the National Hospital Organization of Japan (H30-NHO(kankakuki)-01)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
  • Health Sciences › Health Professions › Speech and Hearing › Hearing Loss and Rehabilitation
Keywords
GJB2, connexin 26, missense mutations, non-syndromic hearing loss, hydrogen bonding, protein crystal structure, molecular pathogenesis
MeSH terms
Connexin 26, Adolescent, Adult, Child, Child, Preschool, Female, Humans, Hydrogen Bonding, Male, Models, Molecular, Connexins, Crystallography, X-Ray, Amino Acid Substitution, Mutation, Missense, Hearing Loss

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