使用全外显子组测序,我们已经鉴定了新的从头杂合pleckstrin同源结构域相互作用蛋白(PHIP)变体,这些变体被预测为有害的,包括一个移码删除,在两名具有发育迟缓共同临床特征的无关患者中,智力残疾,焦虑,低张力,平衡差,肥胖,和畸形特征。PHIP中的无义突变以前与类似的临床特征相关。6q14.1微缺失的患者,包括PHIP,有类似的发育迟缓表型,智力残疾,低张力,肥胖,提示我们患者的表型是功能缺失突变的结果.PHIP生产多种蛋白质产品,例如PHIP1(也称为DCAF14),PHIP,和NDRP。PHIP1是蛋白水解CUL4-DDB1泛素连接酶复合物的多种底物受体之一。CUL4B缺乏与智力残疾有关,中心性肥胖,肌肉萎缩,和畸形特征。与CUL4B缺陷相关的重叠表型表明PHIP突变通过泛素连接酶途径的破坏引起疾病。
Using whole-exome sequencing, we have identified novel de novo heterozygous pleckstrin homology domain-interacting protein (PHIP) variants that are predicted to be deleterious, including a frameshift deletion, in two unrelated patients with common clinical features of developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. A nonsense mutation in PHIP has previously been associated with similar clinical features. Patients with microdeletions of 6q14.1, including PHIP, have a similar phenotype of developmental delay, intellectual disability, hypotonia, and obesity, suggesting that the phenotype of our patients is a result of loss-of-function mutations. PHIP produces multiple protein products, such as PHIP1 (also known as DCAF14), PHIP, and NDRP. PHIP1 is one of the multiple substrate receptors of the proteolytic CUL4-DDB1 ubiquitin ligase complex. CUL4B deficiency has been associated with intellectual disability, central obesity, muscle wasting, and dysmorphic features. The overlapping phenotype associated with CUL4B deficiency suggests that PHIP mutations cause disease through disruption of the ubiquitin ligase pathway.