Human Molecular Genetics Advance Access originally published online on November 20, 2008
Human Molecular Genetics 2009 18(3):556-568; doi:10.1093/hmg/ddn383
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A Runx2 threshold for the cleidocranial dysplasia phenotype
,
Department of Cell Biology, Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655-0106, USA
* To whom correspondence should be addressed. Tel: +1 5088565625; Fax: +1 5088566800; Email: janet.stein{at}umassmed.edu, jane.lian{at}umassmed.edu
Received May 23, 2008; Revised October 9, 2008; Accepted November 10, 2008
Cleidocranial dysplasia (CCD) in humans is an autosomal-dominant skeletal disease that results from mutations in the bone-specific transcription factor RUNX2 (CBFA1/AML3). However, distinct RUNX2 mutations in CCD do not correlate with the severity of the disease. Here we generated a new mouse model with a hypomorphic Runx2 mutant allele (Runx2neo7), in which only part of the transcript is processed to full-length (wild-type) Runx2 mRNA. Homozygous Runx2neo7/neo7 mice express a reduced level of wild-type Runx2 mRNA (55–70%) and protein. This mouse model allowed us to establish the minimal requirement of functional Runx2 for normal bone development. Runx2neo7/neo7 mice have grossly normal skeletons with no abnormalities observed in the growth plate, but do exhibit developmental defects in calvaria and clavicles that persist through post-natal growth. Clavicle defects are caused by disrupted endochondral bone formation during embryogenesis. These hypomorphic mice have altered calvarial bone volume, as observed by histology and microCT imaging, and decreased expression of osteoblast marker genes. The bone phenotype of the heterozygous mice, which have 79–84% of wild-type Runx2 mRNA, is normal. These results show there is a critical gene dosage requirement of functional Runx2 for the formation of intramembranous bone tissues during embryogenesis. A decrease to 70% of wild-type Runx2 levels results in the CCD syndrome, whereas levels >79% produce a normal skeleton. Our findings suggest that the range of bone phenotypes in CCD patients is attributable to quantitative reduction in the functional activity of RUNX2.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, AL 35294, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Li, W. Pan, W. Xu, N. He, X. Chen, H. Liu, L. Darryl Quarles, H. Zhou, and Z. Xiao RUNX2 mutations in Chinese patients with cleidocranial dysplasia Mutagenesis, September 1, 2009; 24(5): 425 - 431. [Abstract] [Full Text] [PDF]
|
|