PMID- 10545612
OWN - NLM
STAT- MEDLINE
DCOM- 19991214
LR  - 20220410
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 12
DP  - 1999 Nov
TI  - CBFA1 mutation analysis and functional correlation with phenotypic variability in
      cleidocranial dysplasia.
PG  - 2311-6
AB  - Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused
      by mutations in the osteoblast-specific transcription factor CBFA1. To correlate 
      CBFA1 mutations in different functional domains with the CCD clinical spectrum,
      we studied 26 independent cases of CCD and a total of 16 new mutations were
      identified in 17 families. The majority of mutations were de novo missense
      mutations that affected conserved residues in the runt domain and completely
      abolished both DNA binding and transactivation of a reporter gene. These, and
      mutations which result in premature termination in the runt domain, produced a
      classic CCD phenotype by abolishing transactivation of the mutant protein with
      consequent haploinsufficiency. We further identified three putative hypomorphic
      mutations (R391X, T200A and 90insC) which result in a clinical spectrum including
      classic and mild CCD, as well as an isolated dental phenotype characterized by
      delayed eruption of permanent teeth. Functional studies show that two of the
      three mutations were hypomorphic in nature and two were associated with
      significant intrafamilial variable expressivity, including isolated dental
      anomalies without the skeletal features of CCD. Together these data show that
      variable loss of function due to alterations in the runt and PST domains of CBFA1
      may give rise to clinical variability, including classic CCD, mild CCD and
      isolated primary dental anomalies.
FAU - Zhou, G
AU  - Zhou G
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, One
      Baylor Plaza, BCM225, 630E, Houston, TX 77030, USA.
FAU - Chen, Y
AU  - Chen Y
FAU - Zhou, L
AU  - Zhou L
FAU - Thirunavukkarasu, K
AU  - Thirunavukkarasu K
FAU - Hecht, J
AU  - Hecht J
FAU - Chitayat, D
AU  - Chitayat D
FAU - Gelb, B D
AU  - Gelb BD
FAU - Pirinen, S
AU  - Pirinen S
FAU - Berry, S A
AU  - Berry SA
FAU - Greenberg, C R
AU  - Greenberg CR
FAU - Karsenty, G
AU  - Karsenty G
FAU - Lee, B
AU  - Lee B
LA  - eng
GR  - AR 45548/AR/NIAMS NIH HHS/United States
GR  - AR44738/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Core Binding Factor Alpha 1 Subunit)
RN  - 0 (DNA, Complementary)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - COS Cells
MH  - Cleidocranial Dysplasia/*genetics
MH  - Core Binding Factor Alpha 1 Subunit
MH  - DNA, Complementary
MH  - Female
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mutagenesis
MH  - *Mutation
MH  - *Neoplasm Proteins
MH  - Pedigree
MH  - Phenotype
MH  - Transcription Factors/*genetics
EDAT- 1999/11/05 00:00
MHDA- 1999/11/05 00:01
CRDT- 1999/11/05 00:00
PHST- 1999/11/05 00:00 [pubmed]
PHST- 1999/11/05 00:01 [medline]
PHST- 1999/11/05 00:00 [entrez]
AID - ddc267 [pii]
AID - 10.1093/hmg/8.12.2311 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Nov;8(12):2311-6. doi: 10.1093/hmg/8.12.2311.