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

American Journal of Human Genetics
Monika OláhováMatthew T Wheeler

Abstract

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 F1FO 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 mi...Continue Reading

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Citations

Apr 10, 2019·Journal of Genetic Counseling·Diane B ZastrowMatthew T Wheeler
Jul 18, 2018·International Journal of Molecular Sciences·Christine Oriel, Paul Lasko
Dec 19, 2018·Cold Spring Harbor Molecular Case Studies·Laure Frésard, Stephen B Montgomery
Oct 12, 2018·The New England Journal of Medicine·Kimberly SplinterUNKNOWN Undiagnosed Diseases Network
Jun 20, 2019·Proceedings of the National Academy of Sciences of the United States of America·Joe CarrollJohn E Walker
Nov 8, 2020·FEBS Letters·Erika Fernandez-Vizarra, Massimo Zeviani
Nov 6, 2020·Cell and Tissue Research·Bala Krishnan BinsilaRaghavendra Bhatta
Nov 17, 2019·Biochemical and Biophysical Research Communications·Hana NuskovaTomas Mracek
Feb 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Tobias E SpikesJohn E Walker
Jan 14, 2021·International Journal of Molecular Sciences·Margherita Protasoni, Massimo Zeviani
Aug 29, 2020·Mitochondrion·Benoit RuchetonAnne Lombès
May 1, 2021·Life·Chiara GalberValentina Giorgio
Aug 8, 2021·International Journal of Molecular Sciences·Paola ZanfardinoVittoria Petruzzella
Aug 25, 2021·The FEBS Journal·Rishi BanerjeeJukka Kallijärvi
Sep 7, 2021·European Journal of Human Genetics : EJHG·Matthew A LinesMichael T Geraghty

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Methods Mentioned

BETA
Biopsy
exome sequencing
transmission electron microscopy
transgenic

Software Mentioned

SWISS
ANNOVAR
SensOmics
DIOPT
Personalis
Genapsys
MODEL
Novoalign
Qbio
Mercury

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