Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PEBP2/CBF is a heterodimeric transcription factor composed of alpha and beta subunits. There are at least three closely related genes, PEBP2alphaA/Cbfa1, AML1/PEBP2alphaB/Cbfa2 and PEBP2alphaC/Cbfa3, encoding the alpha subunit and one beta subunit encoding gene. Structural alterations of AML1 and the beta subunit gene by chromosome translocations are frequently associated with several types of human leukemia. Structural changes of any of these gene products would have potential to affect the function of others. In this study, we isolated the human PEBP2alphaA cDNA by which we mapped the gene to 6p12.3-p21.1. Human chromosome 6p21 is the locus for cleidocranial dysplasia, an autosomal dominant bone disease. Recent gene disruption study revealed that PEBP2alphaA/Cbfa1 plays an essential role in osteogenesis (Komori et al., Cell, 1997, in press). Therefore, a close relationship between human PEBP2alphaA/CBFA1 and this bone disease is strongly implicated.
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PMID:The cDNA cloning of the transcripts of human PEBP2alphaA/CBFA1 mapped to 6p12.3-p21.1, the locus for cleidocranial dysplasia. 923 71

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.
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PMID:PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients. 1068 83

Cleidocranial dysplasia (CCD), an autosomal dominant human bone disease, is thought to be caused by heterozygous mutations in RUNX2/PEBP2alphaA/CBFA1. To understand the mechanism underlying the pathogenesis of CCD, we studied a novel mutant of RUNX2, namely CCDalphaA376, originally identified in a CCD patient. The nonsense mutation, which resulted in a truncated RUNX2 protein, severely impaired RUNX2 transactivation activity. We showed that signal transducers of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) receptors, Smads, interact with RUNX2 in vivo and in vitro and enhance transactivation ability. The truncated RUNX2 protein failed to interact with Smads, and was unable to induce the osteoblast-like phenotype in C2C12 myoblasts following stimulation with BMP. Exogenous expression of Smads 1 and 4 in C2C12 cells stably expressing RUNX2 showed alkaline phosphatase (ALP) activity, suggesting a possible link between Smads and RUNX2, while in C2C12 stably expressing CCDalphaA376, a detectable level of ALP activity failed to be induced. The results suggest that CCDalphaA376 inhibited RUNX2 function in a dominant negative fashion.
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PMID:A RUNX2/PEBP2alphaA/CBFA1 mutation in cleidocranial dysplasia revealing the link between the gene and Smad. 1136 5

Cleidocranial dysplasia (CCD) is an autosomal dominant human bone disease characterized by hypoplastic or aplastic clavicles, wide cranial sutures, supernumerary teeth, short stature, and other skeletal disorders. Recently, various mutations of the core binding factor (CBFA1) gene have been detected in CCD patients. The CBFA1 gene is a member of the runt family of transcription factors. We experienced one Japanese case of CCD with open sutures, hypoplasia of clavicles and brachydactyly, combined with atlant-axis dislocation. We performed the sequence analysis of the CBFA1 gene and detected a missense mutation of R225W in exon 3.
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PMID:A case of a Japanese patient with cleidocranial dysplasia possessing a mutation of CBFA1 gene. 1188 88