title: PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients.
abstract: Cleidocranial dysplasia (CCD) is an autosomal dominant human bone disease whose genetic locus has been located on chromosome 6p21, where the PEBP2alphaA/CBFA1 gene essential for osteogenesis also maps. Previously, several heterozygous mutations in PEBP2alphaA/CBFA1 were found in CCD patients. In this study, we identified six different types of mutations in PEBP2alphaA/CBFA1 in Japanese CCD patients. Four cases were similar to those reported previously: two were nonsense mutations in the Runt domain, one was a hemizygous deletion, and the other was a missense mutation in the Runt domain which abolished the DNA-binding activity of Runx2/PEBP2alphaA/CBFA1. The remaining two mutations were novel: one had a heterozygous gt-to-tt mutation at the splice donor site (gt) between the exon3-intron junction, which resulted in abnormal exon3 skipping, and the other had a mutation in exon7, which led to the introduction of a translational stop codon in the middle of the transactivation domain. Thus, defects in either the DNA-binding domain or transactivation domain of Runx2/PEBP2alphaA/CBFA1 can cause CCD. The results not only provide a strong genetic evidence that mutations involving in PEBP2alphaA/CBFA1 contribute to CCD, but also provide a useful tool to study how Runx2/PEBP2alphaA/CBFA1 plays its pivotal role during osteoblastic differentiation.
authors.affiliation: Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Y W
authors.initials: YW
authors.lastname: Zhang
authors.forename: N
authors.initials: N
authors.lastname: Yasui
authors.forename: N
authors.initials: N
authors.lastname: Kakazu
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: K
authors.initials: K
authors.lastname: Takada
authors.forename: S
authors.initials: S
authors.lastname: Imai
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Nomura
authors.forename: T
authors.initials: T
authors.lastname: Ochi
authors.forename: S
authors.initials: S
authors.lastname: Okuzumi
authors.forename: H
authors.initials: H
authors.lastname: Nogami
authors.forename: T
authors.initials: T
authors.lastname: Nagai
authors.forename: H
authors.initials: H
authors.lastname: Ohashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D002973:Cleidocranial Dysplasia / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007564:Japan; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011485:Protein Binding; D017384:Sequence Deletion; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; C493709:RUNX2 protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D004247:DNA