Dataset Information

Functional Consequences of Pathogenic Variants of the GJB2 Gene (Cx26) Localized in Different Cx26 Domains.

ABSTRACT: One of the most common forms of genetic deafness has been predominantly associated with pathogenic variants in the GJB2 gene, encoding transmembrane protein connexin 26 (Cx26). The Cx26 molecule consists of an N-terminal domain (NT), four transmembrane domains (TM1-TM4), two extracellular loops (EL1 and EL2), a cytoplasmic loop, and a C-terminus (CT). Pathogenic variants in the GJB2 gene, resulting in amino acid substitutions scattered across the Cx26 domains, lead to a variety of clinical outcomes, including the most common non-syndromic autosomal recessive deafness (DFNB1A), autosomal dominant deafness (DFNA3A), as well as syndromic forms combining hearing loss and skin disorders. However, for rare and poorly documented variants, information on the mode of inheritance is often lacking. Numerous in vitro studies have been conducted to elucidate the functional consequences of pathogenic GJB2 variants leading to amino acid substitutions in different domains of Cx26 protein. In this work, we summarized all available data on a mode of inheritance of pathogenic GJB2 variants leading to amino acid substitutions and reviewed published information on their functional effects, with an emphasis on their localization in certain Cx26 domains.

SUBMITTER: Posukh OL

PROVIDER: S-EPMC10604905 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Functional Consequences of Pathogenic Variants of the GJB2 Gene (Cx26) Localized in Different Cx26 Domains.

Posukh Olga L OL Maslova Ekaterina A EA Danilchenko Valeriia Yu VY Zytsar Marina V MV Orishchenko Konstantin E KE

Biomolecules 20231013 10

One of the most common forms of genetic deafness has been predominantly associated with pathogenic variants in the GJB2 gene, encoding transmembrane protein connexin 26 (Cx26). The Cx26 molecule consists of an N-terminal domain (NT), four transmembrane domains (TM1-TM4), two extracellular loops (EL1 and EL2), a cytoplasmic loop, and a C-terminus (CT). Pathogenic variants in the GJB2 gene, resulting in amino acid substitutions scattered across the Cx26 domains, lead to a variety of ...[more]

PMID: 37892203

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Project description:Missense variants are present amongst the healthy population, but some of them are causative of human diseases. A classification of variants associated with "healthy" or "diseased" states is therefore not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences is essential to offer mechanistic explanations of the true impact of pathogenic variants. Here, we have formalised a statistical framework which enables robust probabilistic quantification of variant enrichment across full-length proteins, their domains, and 3D structure-defined regions. Using this framework, we validate and extend previously reported trends of variant enrichment in different protein structural regions (surface/core/interface). By examining the association of variant enrichment with available functional pathways and transcriptomic and proteomic (protein half-life, thermal stability, abundance) data, we have mined a rich set of molecular features which distinguish between pathogenic and population variants: Pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing and are enriched in more abundant proteins. Additionally, rare population variants display features closer to common than pathogenic variants. We validate the association between these molecular features and variant pathogenicity by comparing against existing in silico variant impact annotations. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants and provides the rationale to prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at fraternalilab.kcl.ac.uk/ZoomVar. It allows users to programmatically annotate missense variants with protein structural information and to calculate variant enrichment in different protein structural regions.

Project description:ObjectiveTo evaluate the prognostic value and explore the biological significance of gap junction protein beta 2 (GJB2 or Cx26) in cervical cancer (CC).MethodsWe first compared GJB2 expression between CC and normal tissues using public databases and immunohistochemistry (IHC). Based on The Cancer Genome Atlas data (TCGA cohort, n = 304) and tissue microarray samples (OBC cohort, n = 111), we explored the prognostic value of GJB2 for CC patients using bioinformatics analysis and IHC scoring. To explore the biological significance of GJB2, Gene set enrichment analysis (GSEA) and Gene Ontology (GO) were performed. The impact of GJB2 on the immune microenvironment was analyzed by CIBERSORTx and ESTIMATE algorithms. We finally investigated the relationship between GJB2 and drug sensitivity based on the Genomics of Drug Sensitivity in Cancer (GDSC).ResultsThe expression of GJB2 was significantly increased in CC over normal tissues. Both the TCGA and OBC cohort found that patients with high GJB2 expression had shorter overall survival (OS) time, and high GJB2 expression was the independent risk factor for prognosis (TCGA: HR, 2.566; 95% CI, 1.066-6.180; p = 0.036; OBC: HR, 2.198; 95% CI, 1.019-4.741; p = 0.045). GJB2 was correlated with patient clinical factors such as tumor size and differentiation grade. The p53 signaling pathway and toll-like receptor pathway may be regulated by GJB2. The abundance of various immune cells was significantly different between the low and high GJB2 expression groups. The ImmuneScore was significantly increased in the high GJB2 expression group. In addition, the expression level of GJB2 was positively correlated with the natural log of the half-maximal inhibitory concentration (LN_IC50) value of cisplatin/paclitaxel (Spearman r = 0.238/0.153, p < 0.001).ConclusionGJB2 can serve as a potential prognostic marker of poor survival and a therapeutic target in CC. Moreover, GJB2 may affect the immune microenvironment and is correlated with chemoresistance.

Dataset Information

Functional Consequences of Pathogenic Variants of the GJB2 Gene (Cx26) Localized in Different Cx26 Domains.

Publications

Functional Consequences of Pathogenic Variants of the <i>GJB2</i> Gene (Cx26) Localized in Different Cx26 Domains.

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