Congenital disorders of glycosylation (CDG) represent a wide range of >140 inherited metabolic diseases, continually expanding not only with regards to the number of newly identified causative genes, but also the heterogeneity of the clinical and molecular presentations within each subtype. The deficiency of ATP6AP1, an accessory subunit of the vacuolar H⁺‐ATPase, is a recently characterised N‐ and O‐glycosylation defect manifesting with immunodeficiency, hepatopathy and cognitive impairment. At the cellular level, the latest studies demonstrate a complex disturbance of metabolomics involving peroxisomal function and lipid homeostasis in the patients. Our study delineates a case of two severely affected siblings with a new hemizygous variant c.221T>C (p.L74P) in ATP6AP1 gene, who both died due to liver failure before reaching 1 year of age. We bring novel pathobiochemical observations including the finding of increased reactive oxygen species in the cultured fibroblasts from the older boy, a striking copper accumulation in his liver, as well as describe the impact of the mutation on the protein in different organs, showing a tissue‐specific pattern of ATP6AP1 level and its posttranslational modification.

中文翻译：

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两个兄弟姐妹中 ATP6AP1-CDG 的严重表型，具有导致差异组织特异性 ATP6AP1 蛋白模式、细胞氧化应激和肝铜积累的新突变。

先天性糖基化障碍 (CDG) 代表了超过 140 种遗传代谢疾病的广泛范围，不仅在新发现的致病基因数量方面不断扩大，而且每个亚型内临床和分子表现的异质性也在不断扩大。ATP6AP1（液泡 H ⁺ -ATPase的辅助亚基）的缺陷是最近表征的 N-和 O-糖基化缺陷，表现为免疫缺陷、肝病和认知障碍。在细胞水平上，最新研究表明代谢组学的复杂紊乱涉及患者的过氧化物酶体功能和脂质稳态。我们的研究描述了一个病例，其中两个严重受影响的兄弟姐妹在ATP6AP1 中具有新的半合子变异 c.221T>C (p.L74P)基因，他们都在 1 岁前因肝功能衰竭而死亡。我们带来了新的病理生化观察结果，包括在大男孩培养的成纤维细胞中发现活性氧增加，肝脏中有惊人的铜积累，并描述了突变对不同器官中蛋白质的影响，显示了组织- ATP6AP1 水平的特定模式及其翻译后修饰。