Although CCD is usually caused by mutations leading to haploinsufficiency of RUNX2, the underlying genetic cause remains unresolved in about 25% of cases.
Cleidocranial dysplasia (CCD) is a skeletal dysplasia caused by heterozygous mutations of RUNX2, a gene that is essential for the mineralization of bone and tooth.
In addition, AML3 has an essential role in bone development, as it is required for osteoblast differentiation and is mutated in patients with cleidocranial dysplasia.J.Cell.Biochem.Suppls.32/33:51-58, 1999.
We tested this approach in three patients with complex chromosomal translocations: The first had craniofacial abnormalities and an apparently balanced t(2;3)(p15;q12) translocation; the second has cleidocranial dysplasia (OMIM 119600) associated with a t(2;6)(q22;p12.3) translocation and a breakpoint in RUNX2 on chromosome 6p; and the third has acampomelic campomelic dysplasia (OMIM 114290) associated with a t(5;17)(q23.2;q24) translocation, with a breakpoint upstream of SOX9 on chromosome 17q.
To understand the mechanism underlying the pathogenesis of CCD, we studied a novel mutant of RUNX2, namely CCDalphaA376, originally identified in a CCD patient.
Cleidocranial dysplasia (CCD) is an autosomal dominant disease characterized by skeletal abnormalities which is secondary to haploinsufficiency of the transcription factor Runx2 that plays a role in osteoblast differentiation.
On the one hand, these genotype-phenotype correlations highlight a general, quantitative dependency, by skeleto-dental developments, on the gene dosage of RUNX2, which has hitherto been obscured by extreme clinical diversities of CCD; this gene-dosage effect is presumed to manifest on small reductions in the total RUNX2 activity, by approximately one-fourth of the normal level at minimum.