Craniometaphyseal dysplasia with severe craniofacial involvement shows homozygosity at 6q21‐22.1 locus

Prontera, Paolo; Rogaia, Daniela; Sobacchi, Cristina; Tavares, Vanessa Luiza Romanelli; Passos‐Bueno, Maria Rita; Donti, Emilio

doi:10.1002/ajmg.a.33826

Cited by 10 publications

(4 citation statements)

References 11 publications

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“…Serum calcium (Ca) and phosphate (Pi) levels were reported to be within normal range or slightly decreased in patients with AR CMD. 9,44 Serum Ca and Pi levels in Cx43 +/+ and Cx43 KI/KI mice were comparable, both at ages of 3 and 8 months (Fig. 3b).…”

Section: Effects Of Cx43r239q Mutation On Bone Turnover In Cx43 Ki/ki...mentioning

confidence: 82%

Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia

Chen,

Fujii,

Okabe

et al. 2024

Preprint

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Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and flaring metaphyses of long bones. Many patients with CMD suffer from neurological symptoms. To date, the pathogenesis of CMD is not fully understood. Treatment is limited to decompression surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a R239Q mutation in CX43. Cx43KI/KI mice replicate many features of AR CMD in craniofacial and long bones. In contrast to Cx43+/+ littermates, Cx43KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones, leading to an expanded bone marrow cavity and increased cortical bone thickness. Although formation of Cx43+/+ and Cx43KI/KI resting OCs are comparable, on bone chips the actively resorbing Cx43KI/KI OCs resorb less bone. Cortical bones of Cx43KI/KI mice have an increase in degenerating osteocytes and empty lacunae. Osteocyte dendrite formation is decreased with reduced expression levels of Fgf23, Sost, Tnf-α, IL-1β, Esr1, Esr2, and a lower Rankl/Opg ratio. Female Cx43KI/KI mice display a more severe phenotype. Sexual dimorphism in bone becomes more evident as mice age. Our data show that the CX43R239Q mutation results in mislocalization of CX43 protein and impairment of gap junction and hemichannel activity. Different from CX43 ablation mouse models, the CX43R239Q mutation leads to the AR CMD-like phenotype in Cx43KI/KI mice not only by loss-of-function but also via a not yet revealed dominant function.

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Section: Effects Of Cx43r239q Mutation On Bone Turnover In Cx43 Ki/ki...mentioning

confidence: 82%

Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia

Chen,

Fujii,

Okabe

et al. 2024

Preprint

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“…In addition, this human region was linked to osteoarthritis and rheumatoid arthritis QTLs [45,49]. Mutation in a locus of 6q21 harboring OSTM1 gene was found to be linked to human malignant infantile osteopetrosis and craniometaphyseal dysplasia with severe craniofacial involvement shows hmozygosity at 6q21-q22.1 locus in human [69,70]. Among all the genes detected underlying QTL on chromosome 10, several genes have previously shown to play important functions in bone growth and remodeling (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Fine mapping of bone structure and strength QTLs in heterogeneous stock rat

Alam

Koller

Cañete

et al. 2015

Bone

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We previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3 × 10−6). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis.

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“…Some pedigrees suggest an autosomal recessive (AR) mode of transmission [1,18,19,20,21] and a linkage study has identified a potential locus for the autosomal recessive form of CMD within a 7 cM interval on chromosome 6q21-22 [18]. However, a causative variant responsible for AR CMD could not be identified.…”

Section: Introductionmentioning

confidence: 99%

A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia

Chen

Almeida

et al. 2013

PLoS ONE

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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.

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Craniometaphyseal dysplasia with severe craniofacial involvement shows homozygosity at 6q21‐22.1 locus

Cited by 10 publications

References 11 publications

Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia

Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia

Fine mapping of bone structure and strength QTLs in heterogeneous stock rat

A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia

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