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

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.

Mutations in TIMM50 cause severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology

“…The persistently high excretion of this metabolite has been linked to a group of disorders characterized by defects located at the mitochondrial membrane. An increasing number of disease‐causing mutations in genes encoding for proteins related to the mitochondrial membrane have been reported in patients with 3‐methylglutaconic aciduria (3‐MGA‐uria), including: TAZ (MIM# 300394; Barth et al, ; Bione et al, ), OPA3 (MIM# 606580; Anikster, Kleta, Shaag, Gahl, & Elpeleg, ), DNAJC19 (MIM# 608977; Davey et al, ), ATPAF2 (MIM# 608918; De Meirleir et al, ), TMEM70 (MIM# 612418; Cízková et al, ), ATP5F1E (MIM# 606153; Mayr et al, ), SERAC1 (MIM# 614725; Wortmann et al, ), AGK (MIM# 610345; Aldahmesh, Khan, Mohamed, Alghamdi, & Alkuraya, ; Mayr et al, ), CLPB (MIM# 616254; Capo‐Chichi et al, ; Kanabus et al, ; Saunders et al, ; Wortmann et al, ), HTRA2 (MIM# 606441; Mandel et al, ), QIL1 (MIM# 616658; Guarani et al, ; Zeharia et al, ), TIMM50 (MIM# 607381; Shahrour et al, ), and ATP5F1D (MIM# 603150; Oláhová et al, ). Disorders associated to 3‐MGA‐uria are usually linked to variable mitochondrial respiratory chain defects and abnormal mitochondrial morphology.…”

A toolkit for genetics providers in follow‐up of patients with non‐diagnostic exome sequencing

“…A group with a similar patient contacted us after seeing the abstract. This patient also had a homozygous suspected pathogenic variant (Olahova et al, ) in the ATP5F1D gene. Collaboration followed to assess gene‐disease association and confirm pathogenicity of both variants.…”

“…When combined with the suspected mitochondrial disease etiology, six homozygous variants in six genes were reviewed. A candidate variant was detected in the ATP5F1D [MIM: 603150] gene (c.245C>T, p.Pro82Leu), which had no known disease association at the time (Olahova et al, ).…”

“…Skin fibroblasts from our patient were sent for clinical analysis of respiratory chain complex V activity, which had not been previously assessed (only complex I‐IV were ruled out). This analysis showed qualitatively decreased activity of complex V. The UDN has access to a model organism laboratory, and a fly model was made to knockdown the fly homolog of ATP5F1D (Olahova et al, ). This led to a severe phenotype, which was rescued by wild‐type human ATP5F1D , but only partially rescued by the patient's p.Pro82Leu variant ATP5F1D .…”

Loss-of-function in IRF2BPL is associated with neurological phenotypes

“…Experiments in fruit flies have previously provided experimental support in identifying causal variants for human disease 19,53-55 and these approaches have been an integral part of the UDN. 13,14,16,21,56 The fly ortholog of IRF2BPL is a poorly characterized gene, CG11138 . This gene was studied in the context of epigenetic regulation through biochemical methodologies during embryogenesis, and was named pits ( protein interacting with Ttk69 and Sin3A ).…”