title: Cleidocranial dysplasia with severe parietal bone dysplasia: C-terminal RUNX2 mutations.
abstract: BACKGROUND
  Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. CCD is caused by mutations in the transcription factor RUNX2, which is known to function as a major regulator of bone differentiation. Despite the characterization of 67 unique mutations in 97 individual cases, and the availability of animal models, no obvious genotype-phenotype correlation has emerged.
  
  
  METHODS
  We describe 3 new cases that were ascertained on the basis of a severe calvarial phenotype, that were associated with 3 novel mutations in the C-terminal region of RUNX2 distal to the DNA-binding runt domain. In addition, a review of all previously described cases was undertaken in an effort to standardize mutation nomenclature, characterize the position of known mutations relative to the runt domain, and explore the hypothesis that C-terminal mutations that preserve the runt domain may lead to more-severe craniofacial phenotypes.
  
  
  RESULTS
  Upon mutational analysis of RUNX2, we identified either frameshift or splice-site mutations that affect the C-terminal region of the resultant protein distal to the runt domain.
  
  
  CONCLUSIONS
  In the context of previously described mutations, these cases suggest that C-terminal mutations that preserve the DNA-binding runt domain while disrupting the SMAD 1,2,3,5 binding domain and the nuclear matrix targeting signal may be responsible for the severe phenotype observed.
authors.affiliation: Children's Craniofacial Center, Children's Hospital and Regional Medical Center, Seattle, Washington 98195-6320, USA. mcunnung@u.washington
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Marianne L
authors.initials: ML
authors.lastname: Seto
authors.forename: Anne V
authors.initials: AV
authors.lastname: Hing
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Bull
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hopkin
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Leppig
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002973:Cleidocranial Dysplasia / Q000175:diagnosis* / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D010294:Parietal Bone / Q000002:abnormalities*; D010641:Phenotype; D017354:Point Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; C493709:RUNX2 protein, human