TY - JOUR

T1 - Functional Consequences of Pathogenic Variants of the GJB2 Gene (Cx26) Localized in Different Cx26 Domains

AU - Posukh, Olga L

AU - Maslova, Ekaterina A

AU - Danilchenko, Valeriia Yu

AU - Zytsar, Marina V

AU - Orishchenko, Konstantin E

N1 - This work was supported by the Ministry of Education and Science of the Russian Federation (Grant No. FSUS-2020-0040 to O.L.P., E.A.M., V.Y.D. and K.E.O.) and by the projects of the Institute of Cytology and Genetics SB RAS (Grant No. FWNR-2022-0003 to V.Y.D. and M.V.Z., and Grant No. FWNR-2022-0021 to O.L.P.).

PY - 2023/10/13

Y1 - 2023/10/13

N2 - 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.

AB - 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.

KW - Humans

KW - Connexin 26/genetics

KW - Connexins/genetics

KW - Deafness/genetics

KW - Hearing Loss/genetics

KW - Hearing Loss, Sensorineural/genetics

KW - Mutation

KW - GJB2

KW - hereditary hearing loss

KW - non-synonymous variants

KW - Cx26 domains

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85175014444&origin=inward&txGid=393c2268d4422b34d1c908ab94c7d500

UR - https://www.mendeley.com/catalogue/3f5158ce-28e5-36f1-be16-782749330459/

U2 - 10.3390/biom13101521

DO - 10.3390/biom13101521

M3 - Review article

C2 - 37892203

VL - 13

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 10

M1 - 1521

ER -