Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia
摘要：
Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by hypoplastic or absent clavicles, large fontanelles, dental anomalies and delayed skeletal development. The phenotype is suggestive of a generalized defect in ossification and is one of the most common skeletal dysplasias not associated with disproportionate stature. To date, no genetic determinants of ossification have been identified. CCD has been mapped to chromosome 6p21, where CBFA1, a gene encoding OSF2/CBFA1, a transcriptional activator of osteoblast differentiation, has been localized. Here, we describe two de novo missense mutations, Met175Arg and Ser191Asn, in the OSF2/CBFA1 gene in two patients with CCD. These two mutations result in substitution of highly conserved amino acids in the DNA-binding domain. DNA-binding studies with the mutant polypeptides show that these amino acid substitutions abolish the DNA-binding ability of OSF2/CBFA1 to its known target sequence. Concurrent studies show that heterozygous nonsense mutations in OSF2/CBFA1 also result in CCD, while mice homozygous for the osf2/cbfa1 mull allele exhibit a more severe lethal phenotype. Thus, these results together suggest that CCD is produced by haploinsufficiency of OSF2/CBFA1 and provide direct genetic evidence that the phenotype is secondary to an alteration of osteoblast differentiation.
展开
关键词：
Humans Bone and Bones Osteoblasts Tumor Cells, Cultured Chromosomes, Human, Pair 6 Cleidocranial Dysplasia Transcription Factors DNA Neoplasm Proteins Chromosome Mapping
DOI：
10.1038/ng0797-307
被引量：
年份：
1997
BMJ
Nature
(全网免费下载)
Nature
Springer
万方医学
查看更多
dx.doi.org
Ingenta
NCBI
NCBI
Oxford Univ Press
Europe PMC
Cell Press
AACR
ResearchGate
ProQuest
fasebj.org
annclinlabsci.org
emboj.embopress.org
uthealth.influuent.utsystem.edu
scripts.iucr.org
pubfacts.com
scienceopen.com
onAcademic
SAGE
jcb.rupress.org
molbiolcell.org
dev.biologists.org
bloodjournal.org
www.socolar.com
mcponline.org
mendeley.com
jacionline.org
genesdev.cshlp.org
Nature
(全网免费下载)
通过文献互助平台发起求助，成功后即可免费获取论文全文。
相似文献
参考文献
引证文献
辅助模式
引用
文献可以批量引用啦~
欢迎点我试用！
