A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal DysplasiaReport as inadecuate

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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.

Author: Ying Hu, I-Ping Chen, Salome de Almeida, Valdenize Tiziani, Cassio M. Raposo Do Amaral, Kalpana Gowrishankar, Maria Rita Passos-B

Source: http://plos.srce.hr/


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