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.
Highlights
Craniometaphyseal dysplasia (CMD; MIM #123000) is a rare genetic disorder affecting the skeleton with progressive hyperostosis of craniofacial bones and abnormal modeling of tubular bones
Out of 46,866 homozygous variants 4,895 were non-synonymous. One of these variants, a G to A tansversion (c.716G>A) in gap junction protein alpha-1 (GJA1) (RefSeq NM_000165.3) (Figure 2), which was novel according to dbSNP, the Human Gene Mutation Database (HGMD), 1000 Genomes Project and National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP; approx. 2,200 individuals) data colocalized with the putative recessive CMD locus on chromosome 6q21–q22
The R239Q variant in CONNEXIN 43 (CX43) is located in a phylogenetically highly conserved region, which has been identified as a potential tubulin binding motif (Figure 3) [22]
Summary
Craniometaphyseal dysplasia (CMD; MIM #123000) is a rare genetic disorder affecting the skeleton with progressive hyperostosis of craniofacial bones and abnormal modeling of tubular bones. Craniofacial abnormalities include wide-set eyes, wide nasal bridge, paranasal bossing and prominent mandible. The main feature leading to morbidity is hyperostosis of cranial bones, which can lead to increased intracranial pressure and narrowing of neural foramina [1,2,3,4]. Nerve damage can lead to facial palsy, blindness and deafness. Increased bone formation can further lead to Chiari malformation, compression of the spinal cord and syringomyelia [5,6,7]. The metaphyses of long bones are widened and undertrabeculated, possibly due to insufficient bone remodeling by dysfunctional osteoblasts and osteoclasts [8,9]
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