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A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia.
PLoS One. 2013; 8(8):e73576.Plos

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 Cx43 mutation remain to be elucidated.

Authors+Show Affiliations

Department of Reconstructive Sciences, Center for Regenerative Medicine and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut, United States of America.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23951358

Citation

Hu, Ying, et al. "A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia." PloS One, vol. 8, no. 8, 2013, pp. e73576.
Hu Y, Chen IP, de Almeida S, et al. A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. PLoS ONE. 2013;8(8):e73576.
Hu, Y., Chen, I. P., de Almeida, S., Tiziani, V., Do Amaral, C. M., Gowrishankar, K., Passos-Bueno, M. R., & Reichenberger, E. J. (2013). A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. PloS One, 8(8), e73576. https://doi.org/10.1371/journal.pone.0073576
Hu Y, et al. A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia. PLoS ONE. 2013;8(8):e73576. PubMed PMID: 23951358.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. AU - Hu,Ying, AU - Chen,I-Ping, AU - de Almeida,Salome, AU - Tiziani,Valdenize, AU - Do Amaral,Cassio M Raposo, AU - Gowrishankar,Kalpana, AU - Passos-Bueno,Maria Rita, AU - Reichenberger,Ernst J, Y1 - 2013/08/12/ PY - 2013/04/24/received PY - 2013/07/04/accepted PY - 2013/8/17/entrez PY - 2013/8/21/pubmed PY - 2014/4/16/medline SP - e73576 EP - e73576 JF - PloS one JO - PLoS ONE VL - 8 IS - 8 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23951358/A_novel_autosomal_recessive_GJA1_missense_mutation_linked_to_Craniometaphyseal_dysplasia_ L2 - http://dx.plos.org/10.1371/journal.pone.0073576 DB - PRIME DP - Unbound Medicine ER -