In conclusion, we identified a novel insertion/frameshift mutation in the RUNX2 gene that caused a typical CCD phenotype and altered the biological function of RUNX2(+/m) MSCs.
Although CCD is usually caused by mutations leading to haploinsufficiency of RUNX2, the underlying genetic cause remains unresolved in about 25% of cases.
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.
We demonstrated that a novel mutation (c.549delC) of RUNX2 is associated with CCD in a Chinese family, adding to the repertoire of RUNX2 mutations related to CCD.
The molecular characterization of the novel RUNX2 gene mutation c.580 + 1G > A in an Italian family (a 27-year-old female, her 54-year-old mother and 24-year-old sister) affected by the typical CCD phenotype, which was proven to alter splicing of the RUNX2 messenger RNA, underscoring the contribution of novel altered splicing mechanism to the aetiology of this disease is presented.
We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation.
Cleidocranial dysplasia (CCD, MIM#119600), for which the responsible gene is RUNX2, is a genetic disorder characterized by hypoplasia or aplasia of the clavicles, patent fontanelles, and a short stature.
Deregulated TGFβ or Runx2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss, as seen in human cleidocranial dysplasia.
We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation.
This is the first report that gives evidence that the T420I mutation of RUNX2 is associated with CCD, expanding the spectrum of RUNX2 mutations causing CCD.