Dysregulation of chondrogenesis in human cleidocranial dysplasia.
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.
Zheng
Qiping
Q
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Sebald
Eiman
E
Zhou
Guang
G
Chen
Yuqing
Y
Wilcox
William
W
Lee
Brendan
B
Krakow
Deborah
D
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
D017931:DNA Primers; D014157:Transcription Factors