title: Dysregulation of chondrogenesis in human cleidocranial dysplasia.
abstract: Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia caused by heterozygosity of mutations in human RUNX2. The disorder is characterized by delayed closure of the fontanel and hypoplastic clavicles that result from defective intramembranous ossification. However, additional features, such as short stature and cone epiphyses, also suggest an underlying defect in endochondral ossification. Here, we report observations of growth-plate abnormalities in a patient with a novel RUNX2 gene mutation, a single C insertion (1228insC), which is predicted to lead to a premature termination codon and thus to haploinsufficiency of RUNX2 and the CCD phenotype. Histological analysis of the rib and long-bone cartilages showed a markedly diminished zone of hypertrophy. Quantitative real-time reverse transcription-polymerase chain reaction analysis of limb cartilage RNA showed a 5-10-fold decrease in the hypertrophic chondrocyte molecular markers VEGF, MMP13, and COL10A1. Together, these data show that humans with CCD have altered endochondral ossification due to altered RUNX2 regulation of hypertrophic chondrocyte-specific genes during chondrocyte maturation.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qiping
authors.initials: Q
authors.lastname: Zheng
authors.forename: Eiman
authors.initials: E
authors.lastname: Sebald
authors.forename: Guang
authors.initials: G
authors.lastname: Zhou
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Wilcox
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology*; D020219:Chondrogenesis; D002973:Cleidocranial Dysplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers / Q000235:genetics; D005121:Extremities / Q000473:pathology; D005269:Femur / Q000473:pathology; D005786:Gene Expression Regulation; D006132:Growth Plate / Q000473:pathology; D006801:Humans; D006984:Hypertrophy / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017931:DNA Primers; D014157:Transcription Factors