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一个患有神经发育障碍、小脑萎缩和癫痫的患者,其 PIGK 基因存在一个新型的纯合性变异,该变异由父源单亲二倍体引起。

A novel homozygous variant of the PIGK gene caused by paternal disomy in a patient with neurodevelopmental disorder, cerebellar atrophy, and seizures.

机构信息

Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara, 252-5258, Japan.

Department of Genome Medicine, National Center for Child Health and Development, Tokyo, 157-8535, Japan.

出版信息

J Hum Genet. 2024 Nov;69(11):553-563. doi: 10.1038/s10038-024-01264-3. Epub 2024 Jun 20.

Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins are located at the cell surface by a covalent attachment between protein and GPI embedded in the plasma membrane. This attachment is catalyzed by GPI transamidase comprising five subunits (PIGK, PIGS, PIGT, PIGU, and GPAA1) in the endoplasmic reticulum. Loss of either subunit of GPI transamidase eliminates cell surface localization of GPI-anchored proteins. In humans, pathogenic variants in either subunit of GPI transamidase cause neurodevelopmental disorders. However, how the loss of GPI-anchored proteins triggers neurodevelopmental defects remains largely unclear. Here, we identified a novel homozygous variant of PIGK, NM_005482:c.481A > G,p. (Met161Val), in a Japanese female patient with neurodevelopmental delay, hypotonia, cerebellar atrophy, febrile seizures, hearing loss, growth impairment, dysmorphic facial features, and brachydactyly. The missense variant was found heterozygous in her father, but not in her mother. Zygosity analysis revealed that the homozygous PIGK variant in the patient was caused by paternal isodisomy. Rescue experiments using PIGK-deficient CHO cells revealed that the p.Met161Val variant of PIGK reduced GPI transamidase activity. Rescue experiments using pigk mutant zebrafish confirmed that the p.Met161Val variant compromised PIGK function in tactile-evoked motor response. We also demonstrated that axonal localization of voltage-gated sodium channels and concomitant generation of action potentials were impaired in pigk-deficient neurons in zebrafish, suggesting a link between GPI-anchored proteins and neuronal defects. Taken together, the missense p.Met161Val variant of PIGK is a novel pathogenic variant that causes the neurodevelopmental disorder.

摘要

糖基磷脂酰肌醇(GPI)锚定蛋白通过蛋白与质膜中嵌入的 GPI 之间的共价连接而位于细胞表面。这种附着由内质网中的五亚基(PIGK、PIGS、PIGT、PIGU 和 GPAA1)GPI 转酰胺酶催化。GPI 转酰胺酶的任一亚基缺失都会消除 GPI 锚定蛋白的细胞表面定位。在人类中,GPI 转酰胺酶的任一亚基的致病性变异都会导致神经发育障碍。然而,GPI 锚定蛋白的缺失如何引发神经发育缺陷在很大程度上仍不清楚。在这里,我们在一名患有神经发育迟缓、低张力、小脑萎缩、热性惊厥、听力损失、生长障碍、面部畸形特征和短指畸形的日本女性患者中发现了一种新型的 PIGK 纯合变异体,NM_005482:c.481A > G,p.(Met161Val)。该错义变异在她的父亲中为杂合子,但在她的母亲中则不是。杂合性分析表明,患者中的 PIGK 纯合变异是由父源同二倍体引起的。使用 PIGK 缺陷型 CHO 细胞进行的挽救实验表明,PIGK 的 p.Met161Val 变异降低了 GPI 转酰胺酶活性。使用 pigk 突变型斑马鱼的挽救实验证实,p.Met161Val 变异使 PIGK 丧失了在触觉诱发运动反应中的功能。我们还证明,电压门控钠通道的轴突定位和伴随的动作电位产生在斑马鱼中 pigk 缺陷神经元中受损,提示 GPI 锚定蛋白与神经元缺陷之间存在联系。总之,PIGK 的 p.Met161Val 错义变异是一种导致神经发育障碍的新型致病变异。

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