DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS
DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS
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DOI：
10.1007/s00439-005-1331-y
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发表时间：
2005-09-01
期刊：
影响因子：
5.3
通讯作者：
Rasi, S
中科院分区：
文献类型：
--
作者：
Bartsch, O;Schmidt, S;Rasi, S
Rubinstein-Taybi综合征（RSTS）是一种显性遗传性疾病，以身材矮小、典型面容、拇指和拇宽角、智力低下为特征。RSTS可由染色体微缺失和CREBBP基因的分子突变引起;然而，迄今为止报道的突变相对较少。在这里，我们的目的是确定率的点突变和其他小分子病变在真正的RSTS和可能的轻度变异，通过使用基因组DNA测序。一个连续系列的患者，包括17例患者从我们以前的研究进行了调查。我们在代表三个不同诊断组的总共45名患者中鉴定了19种CREBBP致病突变：（a）30例明确RSTS患者中的17个突变（检出率56.6%），（B）8例患者中有2个突变，具有提示RSTS的特征（“中度或不完全RSTS”，检出率25%），和（c）在7例未确诊的综合征和孤立的RSTS特征的患者中没有突变。一般来说，突变分布没有热点，大多数是独特的;然而，三个复发突变（R370 X，R1664 H和N1978 S）被确定。此外，我们检测到15个不同的基因内多态性，包括两个非同义编码多态性，L551 I和Q2208 H。我们不仅报告了迄今为止RSTS患者CREBBP突变的最高检出率（56.6%），而且报告了中度或不完全RSTS患者的第二个错义突变（N1978S）。先前的研究已经在8 - 12%的患者中确定了CREBBP基因的细胞遗传学缺失，最近，Roelfsema等人报告了92例患者中的3例（3.3%）患有真正的RSTS或类似RSTS的不同综合征的患者中的EP300基因突变。我们在明确RSTS患者中CREBBP分子突变的56.6%检出率支持了RSTS是一种遗传异质性疾病的新概念，此外，表明RSTS可能由CREBBP以外的基因引起，高达30%的病例。
Rubinstein-Taybi syndrome (RSTS) is a distinct dominant disorder characterized by short stature, typical face, broad angulated thumbs and halluces, and mental retardation. The RSTS can be caused by chromosomal microdeletions and molecular mutations in the CREBBP gene; however, relatively few mutations have been reported to date. Here, we aimed to determine the rate of point mutations and other small molecular lesions in true RSTS and possible mild variants, by using genomic DNA sequencing. A consecutive series of patients including 17 patients from our previous study was investigated. We identified 19 causative mutations of CREBBP in a total of 45 patients representing three different diagnostic groups: (a) 17 mutations in 30 patients with unequivocal RSTS (detection rate 56.6%), (b) two mutations in eight patients with features suggestive of RSTS ("moderate or incomplete RSTS", detection rate 25%), and (c) no mutation in seven patients with undiagnosed syndromes and isolated features of RSTS. In general, the mutations were distributed without hot spots and most were unique; however, three recurrent mutations (R370X, R1664H, and N1978S) were identified. Furthermore, we detected 15 different intragenic polymorphisms, including two non-synonymous coding polymorphisms, L551I and Q2208H. We report not only the highest detection rate (56.6%) of CREBBP mutations in patients with RSTS to date, but also the second missense mutation (N1978S) in a patient with moderate or incomplete RSTS. Previous studies have identified cytogenetic deletions in the CREBBP gene in eight to 12% of patients and very recently, Roelfsema et al. reported EP300 gene mutations in three of 92 (3.3%) patients with either true RSTS or different syndromes resembling RSTS. Our 56.6% detection rate of molecular mutations in CREBBP in patients with unequivocal RSTS supports the new concept that RSTS is a genetically heterogeneous disorder and furthermore, indicates that RSTS may be caused by gene/s other than CREBBP in up to 30% of cases.