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Identification of novel CBFA1/RUNX2 mutations causing cleidocranial dysplasia
Author(s) -
Bergwitz C.,
Prochnau A.,
Mayr B.,
Kramer F.J.,
Rittierodt M.,
Berten H.L.,
Hausamen J.E.,
Brabant G.
Publication year - 2001
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/a:1012758925617
Subject(s) - cleidocranial dysplasia , missense mutation , genetics , frameshift mutation , mutation , biology , runx2 , dysplasia , short stature , medicine , transcription factor , supernumerary , anatomy , endocrinology , gene
Core binding factor A1 (CBFA1/RUNX2) is a runt‐like transcription factor essential for osteoblast differentiation. Haplotype insufficiency causes cleidocranial dysplasia (CCD), a syndrome featuring supernumerary tooth buds, delayed tooth eruption, patent fontanels, Wormian bones, short stature, dysplasia of the clavicles, growth retardation and hypoplasia of the distal phalanges. We identified novel CBFA1 / RUNX2 mutations after PCR and direct sequencing of patient leukocyte DNA. In family 1 mother and son are affected by CCD. Both carry the missense mutation R190W (CGG > TGG). This nucleotide change introduced a Bsm I restriction site, which was used to independently confirm the mutation. It was absent in healthy members of the family. Family 2, in which father and daughter are affected by CCD, shows a deletion of nucleotide C821. This deletion causes a frameshift mutation with premature stop after the insertion of 18 aberrant amino acids. Healthy family members did not have this mutation. The clavicular dysplasia was more pronounced with the R190W mutation, while the bone density was markedly reduced in individuals with either mutation, suggesting a previously underemphasized increased risk for osteoporosis in CCD.