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Severe phenotype of ATP6AP1‐CDG in two siblings with a novel mutation leading to a differential tissue‐specific ATP6AP1 protein pattern, cellular oxidative stress and hepatic copper accumulation
Author(s) -
Ondruskova Nina,
Honzik Tomas,
Vondrackova Alzbeta,
Stranecky Viktor,
Tesarova Marketa,
Zeman Jiri,
Hansikova Hana
Publication year - 2020
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12237
Subject(s) - biology , phenotype , mutation , glycosylation , oxidative stress , haploinsufficiency , gene , genetics , protein subunit , proteostasis , microbiology and biotechnology , endocrinology
Abstract 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.