Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia
Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia
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DOI：
10.1016/j.ajhg.2016.02.007
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发表时间：
2016-04-07
影响因子：
9.8
通讯作者：
Murakami, Yoshiko
中科院分区：
文献类型：
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作者：
Makrythanasis, Periklis;Kato, Mitsuhiro;Murakami, Yoshiko
糖基磷脂酰肌醇(GPI)是一种糖脂，可以将各种蛋白质锚定在细胞表面。至少有27个基因参与了GPI锚定蛋白(GPI-AP)的生物合成和运输。到目前为止，已知这些基因中的13个突变会导致遗传性GPI缺陷(IGD)，并且所有这些基因都是以隐性特征遗传的。IGD主要表现为智力障碍、癫痫、面部粗糙和多器官异常。这些症状是由于GPI-APs表面表达减少或GPI结构异常引起的。在这里，我们介绍了五个受影响的个体(来自两个来自埃及和巴基斯坦的近亲家庭和一个来自日本的非血亲家庭)，他们表现出智力残疾、低眼压和早发性癫痫。我们在Pigg中发现了致病变异，Pigg是GPI途径中的一个基因。在近亲家系中发现了c.928C>；T(p.G1n310*)和c.2261+1G>；C纯合变异，而日本人是c.2005C>；T(p.Arg669Cys)的复合杂合子，2.4Mb缺失涉及Pigg。PIGG是一种用乙醇胺磷酸修饰第二甘露糖的酶，在GPI连接到蛋白质后不久就会被移除。这一瞬时修饰的生理意义尚不清楚。用埃及和日本家庭中受影响的个体的B淋巴母细胞，我们发现Pigg活性几乎完全丧失；然而，GPI-AP的表面水平和结构正常，这表明Pigg缺陷的发病机制尚不完全清楚。PIGG致病变异的发现扩大了IGDS的范围，进一步加强了我们对这一致病类别的智能障碍的理解。
Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early -onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.G1n310*) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability.