A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia

• Published in: PloS one Vol. 8; no. 8; p. e73576
• Main Authors: Hu, Ying, Chen, I-Ping, de Almeida, Salome, Tiziani, Valdenize, Do Amaral, Cassio M. Raposo, Gowrishankar, Kalpana, Passos-Bueno, Maria Rita, Reichenberger, Ernst J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.08.2013; Public Library of Science (PLoS)
• Subjects: Abnormalities; Amino Acid Sequence; Biocompatibility; Biomedical materials; Bone dysplasia; Bone remodeling; Bones; C-Terminus; Chondrocytes; Connexin 43; Connexin 43 - chemistry; Connexin 43 - genetics; Consanguinity; Craniofacial Abnormalities - diagnosis; Craniofacial Abnormalities - genetics; Craniometaphyseal dysplasia; Deoxyribonucleic acid; Developmental biology; DNA; Dysplasia; Ethics; Exome; Eye Abnormalities - diagnosis; Eye Abnormalities - genetics; Foot Deformities, Congenital - diagnosis; Foot Deformities, Congenital - genetics; Gap junctions; Genes, Recessive; Genetic aspects; Genetic Association Studies; Genomes; Glutamine; High-Throughput Nucleotide Sequencing; Hospitals; Humans; Low molecular weights; Missense mutation; Molecular Sequence Data; Molecular weight; Mutation; Mutation, Missense; Oculodentodigital dysplasia; Osteoblasts; Osteoclasts; Osteocytes; Pedigree; Phosphates; Proteins; Sequence Alignment; Syndactyly; Syndactyly - diagnosis; Syndactyly - genetics; Tooth Abnormalities - diagnosis; Tooth Abnormalities - genetics; United States > US; Connecticut
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0073576

Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. CMD can be inherited in an autosomal dominant (AD) trait or occur after de novo mutations in the pyrophosphate transporter ANKH. Although the autosomal recessive (AR) form of CMD had been mapped to 6q21-22 the mutation has been elusive. In this study, we performed whole-exome sequencing for one subject with AR CMD and identified a novel missense mutation (c.716G>A, p.Arg239Gln) in the C-terminus of the gap junction protein alpha-1 (GJA1) coding for connexin 43 (Cx43). We confirmed this mutation in 6 individuals from 3 additional families. The homozygous mutation cosegregated only with affected family members. Connexin 43 is a major component of gap junctions in osteoblasts, osteocytes, osteoclasts and chondrocytes. Gap junctions are responsible for the diffusion of low molecular weight molecules between cells. Mutations in Cx43 cause several dominant and recessive disorders involving developmental abnormalities of bone such as dominant and recessive oculodentodigital dysplasia (ODDD; MIM #164200, 257850) and isolated syndactyly type III (MIM #186100), the characteristic digital anomaly in ODDD. However, characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with the recessive Arg239Gln Cx43 mutation. Bone remodeling mechanisms disrupted by this novel Cx43 mutation remain to be elucidated.