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.