Characterization of a p.R76H mutation in Cx50 identified in a Chinese family with congenital nuclear cataract

Connexins form intercellular communication channels, known as gap junctions (GJs), in many tissues/organs. Mutations in connexin genes are found to be linked to various inherited diseases, but the mechanisms are not fully clear. The Arg76 (R76) in Cx50 is fully conserved across the entire connexin family and is a hotspot for five connexin-linked inherited diseases, including Cx50 and Cx46-linked congenital cataract, Cx43-linked oculodentodigital dysplasia, and Cx45-linked cardiac arrhythmias. To better understand the molecular and cellular mechanism of dysfunction caused by R76/75 mutations, we examined the functional status and properties of GJs containing R76 mutations in Cx50 (R76H/C), Cx43 (R76H/S/C), and Cx45 (R75H) with an emphasis on heterotypic GJs in connexin-deficient model cells. All tested mutants showed an impairment of homotypic GJ function reflected by a decreased coupling% and conductance, except for Cx43 R76H/S. These connexin mutants also showed impaired GJ function when paired with a docking compatible connexin, such as Cx50/Cx46 or Cx45/Cx43, except for all mutants on Cx43 which formed functional heterotypic GJs with Cx45. Localization studies on fluorescent protein tagged connexin mutants revealed that Cx45 R75H and Cx43 R76C showed impaired localization. Our homology structure models indicated that mutations of R76/75 in these GJs led to a loss of intra- and/or inter-connexin non-covalent interactions (salt bridges) at the sidechain of this residue, which could contribute to the observed GJ impairments underlying diseases. It is interesting that unlike those disease-linked variants in Cx50 and Cx45, Cx43 can tolerate some variations at R76.

show abstract

Evaluating gap junction variants for a role in pediatric cataract: an overview of the genetic landscape and clinical classification of variants in the GJA3 and GJA8 genes

Jones

Burdon

2023

Expert Review of Ophthalmology

View full text Add to dashboard Cite

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

hi@scite.ai

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

Characterization of a p.R76H mutation in Cx50 identified in a Chinese family with congenital nuclear cataract

Cited by 4 publications

References 21 publications

Four mutations identified in Chinese families with autosomal dominant congenital cataracts by next-generation sequencing

Four mutations identified in Chinese families with autosomal dominant congenital cataracts by next-generation sequencing

Inherited disease-linked arginine76/75 mutants in Cx50 and Cx45 showed impaired homotypic and heterotypic gap junction function, but not Cx43

Evaluating gap junction variants for a role in pediatric cataract: an overview of the genetic landscape and clinical classification of variants in the GJA3 and GJA8 genes

Contact Info

Product

Resources

About