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Title: Biallelic Mutations in ATP5F1D , which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder

ATP synthase, H + transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F 1F O ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodicmore » metabolic decompensation.« less
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Publication Date:
Grant/Contract Number:
AC0576RL01830
Type:
Accepted Manuscript
Journal Name:
American Journal of Human Genetics
Additional Journal Information:
Journal Volume: 102; Journal Issue: 3; Journal ID: ISSN 0002-9297
Publisher:
Elsevier
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH); Wellcome Centre; Austrian Science Fonds; UK National Health Service
Contributing Orgs:
Undiagnosed Diseases Network Consortia
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; mitochondrial disease; complex V; ATP synthase; exome sequencing; oxidative phosphorylation; lactic acidosis; hyperammonemia; 3-methylglutaric aciduria; model organism; fibroblast
OSTI Identifier:
1423326