Mutagenesis Advance Access published online on June 10, 2009
Mutagenesis, doi:10.1093/mutage/gep025
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RUNX2 mutations in Chinese patients with cleidocranial dysplasia
1Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China 2Institute of Clinical Pharmacology, Central South University, Changsha 410078, China 3People's hospital of Mengyin county, Mengyin, Shandong 276200, China 4The Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA 5Pepole's Hospital of Xuzhou, Jiangsu 221002, China 6Pepole's Hospital of Laiwu, Shandong 271100, China
Cleidocranial dysplasia (CCD) is an autosomal dominant bone disease in humans caused by haploinsufficiency of the RUNX2 gene. The RUNX2 has two major isoforms derived from P1 and P2 promoters. Over 90 mutations of RUNX2 have been reported associated with CCD. In our study, DNA samples of nine individuals from three unrelated CCD families were collected and screened for all exons of RUNX2 and 2 kb of P1 and P2 promoters. We identified two point mutations in the RUNX2 gene in Case 1, including a nonsense mutation (c.577C>T) that has been reported previously and a silent substitution (c.240G>A). In vitro studies demonstrated that c.577C>T mutation led to truncated RUNX2 protein production and diminished stimulating effects on mouse osteocalcin promoter activity when compared with full-length Runx2-II and Runx2-I isoforms. These results confirm that loss of function RUNX2 mutation (c.577C>T) in Case 1 family is responsible for its CCD phenotype.
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Received on February 3, 2009; revised on May 6, 2009; accepted on May 11, 2009.