Role of Connexins in Hereditary Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 February 2024) | Viewed by 3385

Special Issue Editor

Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL, USA
Interests: connexin mutation; hereditary disease; PMLD; CMTX1; SNHL

Special Issue Information

Dear Colleagues,

Connexins are a family of transmembrane proteins that form cell–cell channels (gap junctions), enabling the direct passage of ions and small signaling molecules between coupled cells. Connexins have  essential roles in cell differentiation, proliferation, and homeostasis.  In addition to gap junctions, connexins can also form hemi-channels, and recent evidence further suggests involvement in gap junction-independent cellular activities. 

Twenty-two human connexins have been identified, each differing in tissue distribution, expression, and physiological properties.  Mutations in connexins are associated with over 30 inherited genetic diseases, including congenital cataracts, congenital sensorineural hearing loss, non-syndromic deafness, X-linked Charcot–Marie–Tooth disease, hypomyelinating leukodystrophy, Pelizeaus–Merzbacher-like disease, and skin disorders. Within the field of gap junctions, advanced techniques utilizing genetically modified mouse models, optogenetics, exogenous gene delivery systems, and cryo-EM are providing insights into the roles of connexins in normal physiology and diseases as well as potential therapeutics directed at inherited connexin disorders. 

This Special Issue of Biomolecules welcomes the submission of both original research articles and reviews that focus on understanding the mechanisms underlying the role of connexins in inherited genetic diseases.

Dr. Mona M. Freidin
Guest Editor

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Keywords

  • connexin mutation
  • hereditary disease
  • PMLD
  • CMTX1
  • SNHL

Published Papers (2 papers)

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Review

34 pages, 2562 KiB  
Review
Functional Consequences of Pathogenic Variants of the GJB2 Gene (Cx26) Localized in Different Cx26 Domains
by Olga L. Posukh, Ekaterina A. Maslova, Valeriia Yu. Danilchenko, Marina V. Zytsar and Konstantin E. Orishchenko
Biomolecules 2023, 13(10), 1521; https://doi.org/10.3390/biom13101521 - 13 Oct 2023
Cited by 1 | Viewed by 1294
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Role of Connexins in Hereditary Diseases)
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18 pages, 3567 KiB  
Review
Mechanisms of Diseases Associated with Mutation in GJC2/Connexin 47
by Charles K. Abrams
Biomolecules 2023, 13(4), 712; https://doi.org/10.3390/biom13040712 - 21 Apr 2023
Cited by 3 | Viewed by 1560
Abstract
Connexins are members of a family of integral membrane proteins that provide a pathway for both electrical and metabolic coupling between cells. Astroglia express connexin 30 (Cx30)-GJB6 and Cx43-GJA1, while oligodendroglia express Cx29/Cx31.3-GJC3, Cx32-GJB1, and Cx47- [...] Read more.
Connexins are members of a family of integral membrane proteins that provide a pathway for both electrical and metabolic coupling between cells. Astroglia express connexin 30 (Cx30)-GJB6 and Cx43-GJA1, while oligodendroglia express Cx29/Cx31.3-GJC3, Cx32-GJB1, and Cx47-GJC2. Connexins organize into hexameric hemichannels (homomeric if all subunits are identical or heteromeric if one or more differs). Hemichannels from one cell then form cell-cell channels with a hemichannel from an apposed cell. (These are termed homotypic if the hemichannels are identical and heterotypic if the hemichannels differ). Oligodendrocytes couple to each other through Cx32/Cx32 or Cx47/Cx47 homotypic channels and they couple to astrocytes via Cx32/Cx30 or Cx47/Cx43 heterotypic channels. Astrocytes couple via Cx30/Cx30 and Cx43/Cx43 homotypic channels. Though Cx32 and Cx47 may be expressed in the same cells, all available data suggest that Cx32 and Cx47 cannot interact heteromerically. Animal models wherein one or in some cases two different CNS glial connexins have been deleted have helped to clarify the role of these molecules in CNS function. Mutations in a number of different CNS glial connexin genes cause human disease. Mutations in GJC2 lead to three distinct phenotypes, Pelizaeus Merzbacher like disease, hereditary spastic paraparesis (SPG44) and subclinical leukodystrophy. Full article
(This article belongs to the Special Issue Role of Connexins in Hereditary Diseases)
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