Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Am J Hum Genet. 2019 Aug 1;105(2):395-402. doi: 10.1016/j.ajhg.2019.06.009. Epub 2019 Jul 25.
The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.
糖基磷脂酰肌醇（GPI）锚定将超过 150 种蛋白质与细胞表面连接，并存在于所有细胞类型中。这些蛋白质中的许多在神经元发育和功能中起着至关重要的作用。在涉及 GPI 锚定生物合成的 29 个基因中，已有 18 个基因的突变被确定为人类 GPI 生物合成缺陷（GPIBD）的原因。GPIBD 以智力障碍和癫痫发作为其主要特征。GPI 转酰胺酶复合物的一个重要组成部分是 PIGU，以及 PIGK、PIGS、PIGT 和 GPAA1，它们都将 GPI 锚定蛋白（GPI-AP）连接到内质网（ER）中的 GPI 锚上。在这里，我们报道了来自三个无关家庭的五个人中的两个纯合错义突变（c.209T>A [p.Ile70Lys] 和 c.1149C>A [p.Asn383Lys]）。所有个体均表现为全面发育迟缓、严重至重度智力障碍、肌肉张力减退、癫痫发作、脑异常、脊柱侧凸和轻度面部畸形。使用多色流式细胞术，我们确定了 GPI 转酰胺酶缺陷的特征谱。在粒细胞上，该谱包括荧光素标记的前肺烯醇化酶（FLAER）、CD16 和 CD24 的细胞表面表达减少，但 CD55 和 CD59 不变；此外，B 细胞显示出 T5 抗体确定的游离 GPI 锚的表达增加。此外，不同 GPIBD 的计算机辅助面部分析显示出突变发生在 PIGU 和 GPAA1 中的个体之间共享的特征性面部整体形态。我们的发现提高了我们对 GPI 转酰胺酶复合物在神经系统和骨骼系统发育中的作用的理解，并扩展了属于遗传性 GPI 锚定缺陷组的疾病的临床谱。
