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2020

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A NOVEL AUTOSOMAL RECESSIVE GJA1 MISSENSE MUTATION LINKED TO CRANIOMETAPHYSEAL DYSPLASIA

Ying Hu1, I-Ping Chen2, Salome de Almeida3, Valdenize Tiziani4, Cassio M. Raposo Do Amaral5, Kalpana Gowrishankar6, Maria Rita Passos-Bueno7, Ernst J. Reichenberger1*

1 Department of Reconstructive Sciences, Center for Regenerative Medicine and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut, United States of America,
2 Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, Farmington, Connecticut, United States of America,
3 Medical Genetics Service, Centro Hospitalar de Lisboa, Central, Portugal,
4 Universidade Estadual Vale do Acaraú, Brazil,
5 Instituto de Cirurgia Plástica Cranio-facial - SOBRAPAR, Campinas, Brazil,
6 Department of Medical Genetics, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India,
7 Instituto de Biociencias, Universidade de Sao Paulo, São Paulo, Brazil

PLoS One. 2013 Aug 12;8(8):e73576. doi: 10.1371/journal.pone.0073576. eCollection 2013. (artigo)

Abstract
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 Cx43mutation remain to be elucidated.