Division of Medical Genetics, University Children's Hospital and Department of Biomedicine, Basel, Switzerland.
J Med Genet. 2011 Feb;48(2):117-22. doi: 10.1136/jmg.2010.084582. Epub 2010 Oct 30.
Mutations of the SET binding protein 1 gene (SETBP1) on 18q12.3 have recently been reported to cause Schinzel-Giedion syndrome (SGS). As rare 18q interstitial deletions affecting multiple genes including SETBP1 correlate with a milder phenotype, including minor physical anomalies and developmental and expressive speech delay, mutations in SETBP1 are thought to result in a gain-of-function or a dominant-negative effect. However, the consequence of the SETBP1 loss-of-function has not yet been well described.
Microarray-based comparative genomic hybridisation (aCGH) analyses were performed to identify genetic causes for developmental and expressive speech delay in two patients. SETBP1 expression in fibroblasts obtained from one of the patients was analysed by real-time RT-PCR and western blotting. A cohort study to identify nucleotide changes in SETBP1 was performed in 142 Japanese patients with developmental delay.
aCGH analyses identified submicroscopic deletions of less than 1 Mb exclusively containing SETBP1. Both patients show global developmental, expressive language delay and minor facial anomalies. Decreased expression of SETBP1 was identified in the patient's skin fibroblasts. No pathogenic mutation of SETBP1 was identified in the cohort study.
SETBP1 expression was reduced in a patient with SETBP1 haploinsufficiency, indicating that the SETBP1 deletion phenotype is allele dose sensitive. In correlation with the exclusive deletion of SETBP1, this study delimits a milder phenotype distinct from SGS overlapping with the previously described phenotype of del(18)(q12.2q21.1) syndrome including global developmental, expressive language delay and distinctive facial features. These findings support the hypothesis that mutations in SETBP1 causing SGS may have a gain-of-function or a dominant-negative effect, whereas haploinsufficiency or loss-of-function mutations in SETBP1 cause a milder phenotype.
最近有报道称，18q12.3 上 SET 结合蛋白 1 基因（SETBP1）的突变会导致 Schinzel-Giedion 综合征（SGS）。由于罕见的 18q 染色体间缺失影响多个基因，包括 SETBP1，其表型较轻，包括轻微的身体异常、发育和表达性语言延迟，因此推测 SETBP1 的突变会导致功能获得或显性负效应。然而，SETBP1 功能丧失的后果尚未得到很好的描述。
对两名发育性和表达性语言延迟患者进行基于微阵列的比较基因组杂交（aCGH）分析，以确定遗传病因。通过实时 RT-PCR 和 Western blot 分析从其中一名患者的成纤维细胞中分析 SETBP1 的表达。对 142 名日本发育迟缓患者进行了 SETBP1 核苷酸变化的队列研究。
aCGH 分析发现仅含有 SETBP1 的亚微缺失小于 1Mb。两名患者均表现为全面发育迟缓、表达性语言延迟和轻微的面部异常。在患者的皮肤成纤维细胞中发现 SETBP1 的表达减少。在队列研究中未发现 SETBP1 的致病突变。
在 SETBP1 杂合不足的患者中，SETBP1 的表达减少，表明 SETBP1 缺失表型对等位基因剂量敏感。与 SETBP1 的特异性缺失相关，本研究限定了一种与先前描述的 18q12.2q21.1 缺失综合征重叠的较轻表型，包括全面发育迟缓、表达性语言延迟和独特的面部特征。这些发现支持以下假说：导致 SGS 的 SETBP1 突变可能具有功能获得或显性负效应，而 SETBP1 的杂合不足或功能丧失突变则导致较轻的表型。
