Cleidocranial Dysplasia (RUNX2)
| Dred_ID | RD00025 |
| OMIM ID | 600211 |
| Disease name | Cleidocranial Dysplasia |
| Alternative names | Cleidocranial Dysostosis |
| Category | Genetic diseases, Rare diseases, Bone diseases, Fetal diseases, Oral diseases |
| Phenotype | NIH Rare Diseases: Cleidocranial dysplasia (CCD) is a condition that primarily affects the development of the bones and teeth. Characteristic features include underdeveloped or absent collarbones (clavicles); dental abnormalities; and delayed closing of the spaces between the skull bones (fontanels). Other features may include decreased bone density (osteopenia), osteoporosis, hearing loss, bone abnormalities of the hands, and recurrent sinus and ear infections. CCD is caused by changes (mutations) in the RUNX2 gene and inheritance is autosomal dominant. It may be inherited from an affected parent or occur due to a new mutation in the RUNX2 gene. Management may include dental procedures, treatment of sinus and ear infections, use of helmets for high-risk activities, and/or surgery for skeletal problems.
OMIM: The main clinical features of CCD include persistently open skull sutures with bulging calvaria, hypoplasia or aplasia of the clavicles permitting abnormal facility in apposing the shoulders, wide pubic symphysis, short middle phalanx of the fifth fingers, dental anomalies, and often vertebral malformation. See 168550 for a discussion of the combination of cleidocranial dysplasia and parietal foramina. Pycnodysostosis (265800) and mandibuloacral dysplasia (248370) are disorders to be considered in the differential diagnosis of cleidocranial dysplasia. Acroosteolysis and bone sclerosis with tendency to fracture are differentiating features of pycnodysostosis. Mundlos (1999) provided a review of the clinical features of cleidocranial dysplasia and the molecular basis of this disorder. |
| Miscellaneouse | OMIM: one third of patients represent new mutations |
| Prevalence | Prevalence: 1-9/1000000 (Worldwide),1-9/1000000 (Europe),1-9/100000 (United States) [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | N/A |
| Evidence | Strong |
| Gene symbol | RUNX2 |
| Alias symbols | CCD; AML3; CCD1; CLCD; OSF2; CBFA1; OSF-2; PEA2aA; PEBP2aA; CBF-alpha-1 |
| Gene name | runt-related transcription factor 2 |
| Gene map locus | 6p21; chr6:45,328,157-45,664,349(+) |
| Ensembl Gene ID | ENSG00000124813 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016] |
| Repeat unit | GCN |
| Normal repeat copies | 17 |
| Pathogenic repeat copies | ≥27 |
| Gene | RUNX2 |
| Repeat location | CDS |
| Chromosome locus | chr6:45422751-45422804 (+) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | Cleidocranial dysplasia (CCD) is caused by heterozygous loss-of-function mutation in the RUNX2 gene (600211), encoding transcription factor CBFA1, on chromosome 6p21. Heterozygous duplication in RUNX2 resulting in a gain of function causes metaphyseal dysplasia and maxillary hypoplasia with or without brachydactyly.The RUNX2 gene encodes a Runt-related transcription factor. [By OMIM]
A novel 27Q variant caused CCD by downregulating the transactivation activity of the RUNX2 protein. [By PMID: 25852448] |
| Pathway annotation | Reactome, KEGG |
| PMID | 9182765 |
| Authors | Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR |
| Title | Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia |
| Journal | Cell. 89(5):773-9 |
| Year | 1997 |
| PMID | 12162506 |
| Authors | Vaughan T, Pasco JA, Kotowicz MA, Nicholson GC, Morrison NA |
| Title | Alleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fracture |
| Journal | J Bone Miner Res. 17(8):1527-34 |
| Year | 2002 |