Genetic heterogeneity in Rubinstein-Taybi syndrome:: Mutations in both the CBP and EP300 genes cause disease

被引:318
作者
Roelfsema, JH
White, SJ
Ariyürek, Y
Bartholdi, D
Niedrist, D
Papadia, F
Bacino, CA
den Dunnen, JT
van Ommen, GJB
Breuning, MH
Hennekam, RC
Peters, DJM
机构
[1] Leiden Univ, Med Ctr, Sylvius Lab, Ctr Human & Clin Genet, NL-2333 AL Leiden, Netherlands
[2] Univ Zurich, Inst Med Genet, Zurich, Switzerland
[3] Pediat Hosp Giovanni XXIII, Dept Metab Dis & Clin Genet, Bari, Italy
[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[5] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands
关键词
D O I
10.1086/429130
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
CREB-binding protein and p300 function as transcriptional coactivators in the regulation of gene expression through various signal-transduction pathways. Both are potent histone acetyl transferases. A certain level of CREB-binding protein is essential for normal development, since inactivation of one allele causes Rubinstein-Taybi syndrome (RSTS). There is a direct link between loss of acetyl transferase activity and RSTS, which indicates that the disorder is caused by aberrant chromatin regulation. We screened the entire CREB-binding protein gene (CBP) for mutations in patients with RSTS by using methods that find point mutations and larger rearrangements. In 92 patients, we were able to identify a total of 36 mutations in CBP. By using multiple ligation-dependent probe amplification, we found not only several deletions but also the first reported intragenic duplication in a patient with RSTS. We extended the search for mutations to the EP300 gene and showed that mutations in EP300 also cause this disorder. These are the first mutations identified in EP300 for a congenital disorder.
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页码:572 / 580
页数:9
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