BACKGROUND Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage). RESULTS We addressed the hypothesis that disease-associated variants in either the Synthesis stage or Transamidase+Remodeling-stage GPI pathway genes have distinct phenotypic spectra. We reviewed clinical data from 58 publications describing 152 individual patients and encoded the phenotypic information using the Human Phenotype Ontology (HPO). We showed statistically significant differences between the Synthesis and Transamidase+Remodeling Groups in the frequencies of phenotypes in the musculoskeletal system, cleft palate, nose phenotypes, and cognitive disability. Finally, we hypothesized that phenotypic defects in the IGDs are likely to be at least partially related to defective GPI anchoring of their target proteins. Twenty-two of one hundred forty-two proteins that receive a GPI anchor are associated with one or more Mendelian diseases and 12 show some phenotypic overlap with the IGDs, represented by 34 HPO terms. Interestingly, GPC3 and GPC6, members of the glypican family of heparan sulfate proteoglycans bound to the plasma membrane through a covalent GPI linkage, are associated with 25 of these phenotypic abnormalities. CONCLUSIONS IGDs associated with Synthesis and Transamidase+Remodeling stages of the GPI biosynthesis pathway have significantly different phenotypic spectra. GPC2 and GPC6 genes may represent a GPI target of general disruption to the GPI biosynthesis pathway that contributes to the phenotypes of some IGDs.

中文翻译：

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与合成和转酰胺酶+重塑糖基磷脂酰肌醇（GPI）锚定生物合成基因突变相关的显着不同的临床表型。


背景技术糖基磷脂酰肌醇（GPI）生物合成途径的缺陷可导致一组先天性糖基化疾病，称为遗传性GPI缺陷（IGD）。迄今为止，IGD 中已发现 GPI 生物合成途径中 29 个基因中的 22 个存在缺陷。生物合成途径的早期阶段组装 GPI 锚（合成阶段），后期将 GPI 锚转移到内质网 (ER) 中的新生肽（转酰胺酶阶段），利用脂肪酸重塑稳定 ER 膜中的锚然后将 GPI 锚定蛋白运输到细胞表面（重塑阶段）。结果我们提出了这样的假设：合成阶段或转酰胺酶+重塑阶段 GPI 途径基因中的疾病相关变异具有不同的表型谱。我们回顾了描述 152 名患者的 58 篇出版物的临床数据，并使用人类表型本体 (HPO) 对表型信息进行编码。我们发现合成组和转酰胺酶+重塑组之间在肌肉骨骼系统、腭裂、鼻子表型和认知障碍的表型频率方面存在统计学显着差异。最后，我们假设 IGD 的表型缺陷可能至少部分与其目标蛋白的 GPI 锚定缺陷有关。接受 GPI 锚定的 142 个蛋白质中有 22 个与一种或多种孟德尔疾病相关，其中 12 个显示出与 IGD 的一些表型重叠，由 34 个 HPO 术语表示。有趣的是，GPC3 和 GPC6 是硫酸乙酰肝素蛋白聚糖磷脂酰肌醇蛋白聚糖家族的成员，通过共价 GPI 连接与质膜结合，与其中 25 种表型异常相关。 结论 与 GPI 生物合成途径的合成和转酰胺酶+重塑阶段相关的 IGD 具有显着不同的表型谱。 GPC2 和 GPC6 基因可能代表 GPI 生物合成途径全面破坏的 GPI 靶点，从而导致某些 IGD 的表型。