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.
J Inherit Metab Dis
; 43(4): 694-700, 2020 07.
Article
en En
| MEDLINE
| ID: mdl-32216104
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Trastornos Congénitos de Glicosilación
/
Cobre
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ATPasas de Translocación de Protón Vacuolares
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Síndromes de Inmunodeficiencia
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Hepatopatías
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Humans
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Infant
/
Male
Idioma:
En
Revista:
J Inherit Metab Dis
Año:
2020
Tipo del documento:
Article
País de afiliación:
República Checa