GJA1mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype

Abstract

The predominantly autosomal dominant disorder, oculodentodigital dysplasia (ODDD) has high penetrance with intra-and interfamilial phenotypic variability. Abnormalities observed in ODDD affect the eye, dentition, and digits of the hands and feet. Patients present with a characteristic facial appearance, narrow nose, and hypoplastic alae nasi. Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur as well as conductive hearing loss, cardiac defects, and anomalies of the skin, hair, and nails. In 2003, our analysis of 17 ODDD families revealed that each had a different mutation within the human gap junction alpha 1 (GJA1) gene which encodes the protein connexin 43 (Cx43). Since then at least 17 publications have identified an additional 26 GJA1 mutations and in this study, we present 28 new cases with 18 novel GJA1 mutations. We include tables summarizing the 62 known GJA1 nucleotide changes leading to Cx43 protein alterations and the phenotypic information available on 177 affected individuals from 54 genotyped families. Mutations resulting in ODDD occur in each of the nine domains of the Cx43 protein, and we review our functional experiments and those in the literature, examining the effects of 13 different Cx43 mutations upon gap junction activity.

Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

“…Connexin-43 is the major protein of gap junctions in the heart, and gap junctions are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. Mutations in this gene have also been found in deafness 20 and in palmoplantar keratoderma. 21 …”

Green Fluorescent Protein Changes the Conductance of Connexin 43 (Cx43) Hemichannels Reconstituted in Planar Lipid Bilayers

“…1 Both authors contributed equally to this work. 2 abnormalities of ocular, nasal, and dental structures as well as a few neuronal dysfunctions (11). The synthesis, maturation, and trafficking of connexin isoforms have been visualized in several studies by tagging the green fluorescent protein to the C-terminal end of connexins (12,13).…”

Complex formation between calmodulin and a peptide from the intracellular loop of the gap junction protein connexin43: Molecular conformation and energetics of binding

“…Compared to the peptide previously used, this shorter peptide is missing, for example, two glycine and two glutamate residues, which can be assumed to be of little relevance to CaM binding. It should be noted that within the CBD and in the immediate vicinity of it, several characterized ODDD mutations are present, which could also affect CaM binding ( Figure 1A) [3]. From the analysis of enthalpy at different temperatures, we could estimate the heat capacity of the binding reaction.…”

“…While the mutations are spread throughout the protein, a large fraction of characterized mutations in oculodentodigital dysplasia (ODDD) is found in the intracellular loop [2,3]. Also other connexins are disease-linked; for example, cx32 mutations cause Xlinked Charcot-Marie-Tooth disease that severely affects the myelin sheath in the nervous system [4,5].…”