Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia

Abstract

Gap junctions are assemblies of intercellular channels that regulate a variety of physiologic and developmental processes through the exchange of small ions and signaling molecules. These channels consist of connexin family proteins that allow for diversity of channel composition and conductance properties. The human connexin 43 gene, or GJA1, is located at human chromosome 6q22-q23 within the candidate region for the oculodentodigital dysplasia locus. This autosomal dominant syndrome presents with craniofacial (ocular, nasal, and dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration. Syndactyly type III and conductive deafness can occur in some cases, and cardiac abnormalities are observed in rare instances. We found mutations in the GJA1 gene in all 17 families with oculodentodigital dysplasia that we screened. Sixteen different missense mutations and one codon duplication were detected. These mutations may cause misassembly of channels or alter channel conduction properties. Expression patterns and phenotypic features of gja1 animal mutants, reported elsewhere, are compatible with the pleiotropic clinical presentation of oculodentodigital dysplasia.

Figure 1

ODDD phenotype. Across the top are an adult, a teenager, and a child with microcornea, narrow nose, and/or hypoplastic alae nasi. Across the bottom are additional features: partial ano- and microdontia and enamel hypoplasia, syndactyly, and clinodactyly. The child’s hand had surgical correction of the fourth and fifth finger syndactyly. Note that the child has a mild facial phenotype, but significant digital involvement, as shown in the bottom two right panels. The individuals in the top and bottom left panels are brothers with the Y17S mutation. The teenager has a G22E mutation, and the child has an Y98C mutation.

Figure 2

Sequences of 17 GJA1 mutations found in families affected with ODDD. The top panels show the heterozygous mutations, with the exception of the sequence of the cloned duplication, 154_156dupTTT, and the bottom panels show the control sequences.

Figure 3

Diagram of the GJA1 protein. Locations of the amino acid changes are shown. The first and last amino acids of the protein and of each transmembrane domain are indicated as predicted by the program TMpred (see the TMpred Web site).

Figure 4

Amino acid conservation in connexins. The amino acids of GJA1 that are affected in ODDD are aligned to the corresponding amino acids in gja1 in other species and in other human connexins. Accession numbers given (from NCBI's Entrez-Protein Web site) are for the versions used in the alignment. Connexin amino acid alignments were performed using the ClustalW program (see ClustalW Web site). Proteins are ordered according to homology. Gray shading indicates amino acid differences from the human GJA1 protein. Darker shading indicate amino acids observed only once in the connexins.