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Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation

Zhao, F; Weismann, C G LU ; Satoda, M; Pierpont, M E; Sweeney, E; Thompson, E M and Gelb, B D (2001) In American Journal of Human Genetics 69(4). p.695-703
Abstract

To elucidate further the role, in normal development and in disease pathogenesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we studied eight patients with Char syndrome and their families. Four novel mutations were identified, three residing in the basic domain, which is responsible for DNA binding, and a fourth affecting a conserved PY motif in the transactivation domain. Functional analyses of the four mutants disclosed that two, R225C and R225S, failed to bind target sequence in vitro and that all four had dominant negative effects when expressed in eukaryotic cells. Our present findings, combined with data about two previously identified TFAP2B mutations, show that dominant negative effects consistently appear to... (More)

To elucidate further the role, in normal development and in disease pathogenesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we studied eight patients with Char syndrome and their families. Four novel mutations were identified, three residing in the basic domain, which is responsible for DNA binding, and a fourth affecting a conserved PY motif in the transactivation domain. Functional analyses of the four mutants disclosed that two, R225C and R225S, failed to bind target sequence in vitro and that all four had dominant negative effects when expressed in eukaryotic cells. Our present findings, combined with data about two previously identified TFAP2B mutations, show that dominant negative effects consistently appear to be involved in the etiology of Char syndrome. Affected individuals in the family with the PY motif mutation, P62R, had a high prevalence of patent ductus arteriosus but had only mild abnormalities of facial features and no apparent hand anomalies, a phenotype different from that associated with the five basic domain mutations. This genotype-phenotype correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.

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author
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published
keywords
3T3 Cells, Abnormalities, Multiple/genetics, Amino Acid Motifs, Animals, Child, Cross-Linking Reagents/metabolism, DNA/genetics, DNA-Binding Proteins/chemistry, Ductus Arteriosus, Patent/genetics, Fingers/abnormalities, Genotype, Humans, Male, Mice, Mutation/genetics, Phenotype, Protein Binding, Protein Structure, Tertiary, Syndrome, Transcription Factor AP-2, Transcription Factors/chemistry, Transcriptional Activation, Transfection
in
American Journal of Human Genetics
volume
69
issue
4
pages
9 pages
publisher
Cell Press
external identifiers
  • scopus:0034836484
ISSN
0002-9297
DOI
10.1086/323410
language
English
LU publication?
no
id
c603803c-9e83-4c02-ae5a-77009b2b0345
date added to LUP
2019-01-25 14:48:16
date last changed
2019-11-13 05:25:22
@article{c603803c-9e83-4c02-ae5a-77009b2b0345,
  abstract     = {<p>To elucidate further the role, in normal development and in disease pathogenesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we studied eight patients with Char syndrome and their families. Four novel mutations were identified, three residing in the basic domain, which is responsible for DNA binding, and a fourth affecting a conserved PY motif in the transactivation domain. Functional analyses of the four mutants disclosed that two, R225C and R225S, failed to bind target sequence in vitro and that all four had dominant negative effects when expressed in eukaryotic cells. Our present findings, combined with data about two previously identified TFAP2B mutations, show that dominant negative effects consistently appear to be involved in the etiology of Char syndrome. Affected individuals in the family with the PY motif mutation, P62R, had a high prevalence of patent ductus arteriosus but had only mild abnormalities of facial features and no apparent hand anomalies, a phenotype different from that associated with the five basic domain mutations. This genotype-phenotype correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.</p>},
  author       = {Zhao, F and Weismann, C G and Satoda, M and Pierpont, M E and Sweeney, E and Thompson, E M and Gelb, B D},
  issn         = {0002-9297},
  keyword      = {3T3 Cells,Abnormalities, Multiple/genetics,Amino Acid Motifs,Animals,Child,Cross-Linking Reagents/metabolism,DNA/genetics,DNA-Binding Proteins/chemistry,Ductus Arteriosus, Patent/genetics,Fingers/abnormalities,Genotype,Humans,Male,Mice,Mutation/genetics,Phenotype,Protein Binding,Protein Structure, Tertiary,Syndrome,Transcription Factor AP-2,Transcription Factors/chemistry,Transcriptional Activation,Transfection},
  language     = {eng},
  number       = {4},
  pages        = {695--703},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation},
  url          = {http://dx.doi.org/10.1086/323410},
  volume       = {69},
  year         = {2001},
}