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GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype
Author(s) -
Paznekas William A.,
Karczeski Barbara,
Vermeer Sascha,
Lowry R. Brian,
Delatycki Martin,
Laurence Faivre,
Koivisto Pasi A.,
Van Maldergem Lionel,
Boyadjiev Simeon A.,
Bodurtha Joann N.,
Wang Jabs Ethylin
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20958
Subject(s) - biology , genetics , connexin , phenotype , palmoplantar keratoderma , mutation , penetrance , gene , gap junction , intracellular
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. Hum Mutat 0, 1–10, 2009. © 2009 Wiley‐Liss, Inc.