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

Undiagnosed Diseases Network

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 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 episodic metabolic decompensation.

Original languageEnglish (US)
Pages (from-to)494-504
Number of pages11
JournalAmerican Journal of Human Genetics
Volume102
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Mitochondrial Diseases
Adenosine Triphosphate
Mitochondrial Proton-Translocating ATPases
Head
Hyperammonemia
Phenotype
Lethargy
Mutation
Proton-Translocating ATPases
Genetic Models
Brain Diseases
Acidosis
Diptera
Drosophila
Protons
Fibroblasts
Skin
Brain
oligomycin sensitivity-conferring protein
3-Methylglutaconic Aciduria

Keywords

  • 3-methylglutaric aciduria
  • ATP synthase
  • complex V
  • exome sequencing
  • fibroblast
  • hyperammonemia
  • lactic acidosis
  • mitochondrial disease
  • model organism
  • oxidative phosphorylation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. / Undiagnosed Diseases Network.

In: American Journal of Human Genetics, Vol. 102, No. 3, 01.03.2018, p. 494-504.

Research output: Contribution to journalArticle

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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 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 episodic metabolic decompensation.",
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AU - Undiagnosed Diseases Network

AU - Oláhová, Monika

AU - Yoon, Wan Hee

AU - Thompson, Kyle

AU - Jangam, Sharayu

AU - Fernandez, Liliana

AU - Davidson, Jean M.

AU - Kyle, Jennifer E.

AU - Grove, Megan E.

AU - Fisk, Dianna G.

AU - Kohler, Jennefer N.

AU - Holmes, Matthew

AU - Dries, Annika M.

AU - Huang, Yong

AU - Zhao, Chunli

AU - Contrepois, Kévin

AU - Zappala, Zachary

AU - Frésard, Laure

AU - Waggott, Daryl

AU - Zink, Erika M.

AU - Kim, Young Mo

AU - Heyman, Heino M.

AU - Stratton, Kelly G.

AU - Webb-Robertson, Bobbie Jo M.

AU - Adams, David R.

AU - Alejandro, Mercedes E.

AU - Allard, Patrick

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Balasubramanyam, Ashok

AU - Barseghyan, Hayk

AU - Batzli, Gabriel F.

AU - Beggs, Alan H.

AU - Behnam, Babak

AU - Bican, Anna

AU - Bick, David P.

AU - Birch, Camille L.

AU - Bonner, Devon

AU - Boone, Braden E.

AU - Bostwick, Bret L.

AU - Briere, Lauren C.

AU - Brown, Donna M.

AU - Brush, Matthew

AU - Burke, Elizabeth A.

AU - Burrage, Lindsay C.

AU - Chen, Shan

AU - Clark, Gary D.

AU - Coakley, Terra R.

AU - Cogan, Joy D.

AU - Haendel, Melissa

AU - Koeller, David

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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 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 episodic metabolic decompensation.

AB - 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 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 episodic metabolic decompensation.

KW - 3-methylglutaric aciduria

KW - ATP synthase

KW - complex V

KW - exome sequencing

KW - fibroblast

KW - hyperammonemia

KW - lactic acidosis

KW - mitochondrial disease

KW - model organism

KW - oxidative phosphorylation

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