Zimmermann Nicole, Acosta Ana Maria Bravo Ferrer, Kohlhase Jürgen, Bartsch Oliver
Institute for Human Genetics, Johannes Gutenberg-University, Mainz, Germany.
Eur J Hum Genet. 2007 Aug;15(8):837-42. doi: 10.1038/sj.ejhg.5201791. Epub 2007 Feb 14.
The Rubinstein-Taybi syndrome (RSTS, MIM 180849), a dominant Mendelian disorder with typical face, short stature, skeletal abnormalities, and mental retardation, is usually caused by heterozygous mutations of the CREBBP gene, but recently, EP300 gene mutations were reported in three individuals. Using quantitative PCR (for the CREBBP and EP300 genes) and genomic sequencing (for the EP300 gene), we studied here 13 patients who had shown no mutation after genomic sequencing of the CREBBP gene in a previous investigation. Two new disease-causing mutations were identified, including a partial deletion of CREBBP and a 1-bp deletion in EP300, c.7100delC (p.P2366fsX2401). The 1-bp deletion represents the fourth EP300 mutation reported to date and was identified in a patient with non-classical RSTS. Based on the very similar structure of the CREBBP and EP300 genes and the higher rate of single-nucleotide polymorphisms in EP300 (2.23 per individual) as compared to CREBBP (0.71 per individual) (P>0.001, Wilcoxon test), it may be assumed that EP300 gene mutations should be as frequent as CREBBP gene mutations. Based on the location of the EP300 gene mutations identified so far (outside the histone acetyl transferase domain) and the observed (although not very striking) phenotypical differences with the EP300 mutations, we propose that most EP300 mutations could be associated with other phenotypes, not classical RSTS.
鲁宾斯坦-泰比综合征(RSTS,MIM 180849)是一种孟德尔显性疾病,具有典型面容、身材矮小、骨骼异常和智力发育迟缓等症状,通常由CREBBP基因的杂合突变引起,但最近有报道称在三名个体中发现了EP300基因突变。我们使用定量PCR(针对CREBBP和EP300基因)和基因组测序(针对EP300基因),对之前一项研究中CREBBP基因基因组测序后未发现突变的13名患者进行了研究。鉴定出两个新的致病突变,包括CREBBP的部分缺失和EP300中的一个1bp缺失,即c.7100delC(p.P2366fsX2401)。该1bp缺失是迄今为止报道的第四个EP300突变,在一名非典型RSTS患者中被发现。基于CREBBP和EP300基因非常相似的结构以及EP300中较高的单核苷酸多态性发生率(每人2.23个),与CREBBP(每人0.71个)相比(P>0.001,Wilcoxon检验),可以推测EP300基因突变应与CREBBP基因突变一样频繁。基于目前鉴定出的EP300基因突变的位置(在组蛋白乙酰转移酶结构域之外)以及观察到的(尽管不太明显)与EP300突变相关的表型差异,我们提出大多数EP300突变可能与其他表型相关,而非经典的RSTS。