Johnstone Devon L, Nguyen Thi-Tuyet-Mai, Murakami Yoshiko, Kernohan Kristin D, Tétreault Martine, Goldsmith Claire, Doja Asif, Wagner Justin D, Huang Lijia, Hartley Taila, St-Denis Anik, le Deist Françoise, Majewski Jacek, Bulman Dennis E, Kinoshita Taroh, Dyment David A, Boycott Kym M, Campeau Philippe M
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H8L1, Canada.
Research Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec H3T1C5, Canada.
Hum Mol Genet. 2017 May 1;26(9):1706-1715. doi: 10.1093/hmg/ddx077.
There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.
已知有超过150种人类蛋白质通过糖基磷脂酰肌醇（GPI）锚定在细胞表面。这些蛋白质在发育过程中发挥着多种重要作用，尤其是在神经发生过程中。毫不奇怪，GPI锚生物合成和重塑途径中的突变会导致多种发育障碍。这组病症被称为遗传性GPI缺陷（IGD），是先天性糖基化障碍的一个亚组；它们表现出多种不同的表型，通常包括癫痫发作、肌张力减退和智力残疾。在此，我们报告了两名患有磷脂酰肌醇聚糖锚生物合成P类（PIGP）基因（NM_153681.2：c.74T＞C；p.Met25Thr和c.456delA；p.Glu153AsnFs*34）复合杂合变异的兄弟姐妹。PIGP编码催化GPI锚生物合成第一步的酶的一个亚基。两个孩子均表现出早发性难治性癫痫发作、肌张力减退和严重的全面发育迟缓，这让人联想到其他IGD表型。对患者细胞进行的功能研究显示PIGP mRNA水平降低，以及与之相关的GPI锚定细胞表面蛋白减少，而野生型PIGP的外源性表达可挽救这种情况。这项工作将PIGP基因突变与一种新型常染色体隐性IGD联系起来，并扩展了我们对PIG基因在人类发育中作用的认识。
