Mitochondrial epileptic encephalopathy, 3‐methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations

Abstract

Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.

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

“…In contrast, the patient reported by Reyes et al () harbors a nonsense mutation (p.Ser122Ter) in one allele, encoding for a potentially truncated protein that is likely not expressed under physiological conditions, together with a missense mutation (p.Gly190Ala) on the other allele that maps to the conserved transmembrane domain of the protein. The clinical progression of our patient was also different and was similar to the initially reported TIMM50 patients, who also had missense mutations affecting amino acids of the intermembrane portion of the protein (Shahrour et al, ). In contrast, the patient of Reyes et al () showed a severe and rapid progression of the disease, leading to death at 2 years of age.…”

“…Mutations in TIMM50 have been recently identified in three unrelated families (Reyes et al, ; Shahrour et al, ). The clinical and biochemical phenotypes of the previously described individuals were similar to those of the patient in this study, except that 3‐MGA‐uria was not observed in one of them (Reyes et al, ), and that cardiac involvement and neutropenia were not reported in any of the previous cases.…”

“…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.…”

Mutations in TIMM50 compromise cell survival in OxPhos‐dependent metabolic conditions

“…Likewise, partial depletion of Tim50 in yeast resulted in mtHsp60 import impairment without any effect on ACC (Yamamoto et al , ). Although a pathogenic mutation in human TIMM50 failed to be associated with import impairment (Shahrour et al , ), we noticed that Shahrour et al () used yeast as an in vivo model system to validate the mutation, despite the fact that human TIMM50 cannot rescue the phenotype of yeast ΔTim50 and the global conservation between these two proteins is very poor.…”

“…Sengers syndrome is an autosomal recessive disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and exercise intolerance caused by mutations in AGK (Aldahmesh et al , ; Mayr et al , ; Haghighi et al , ), encoding a protein only recently described as a component of the TIM22 complex (Vukotic et al , ). Finally, mutations in TIMM50 , coding for a core subunit of the TIM23 complex, have been reported in siblings from two unrelated families with severe intellectual disability and seizures, slightly elevated lactate levels, 3‐methylglutaconic aciduria and, in one subject, deficiency of mitochondrial complex V (Shahrour et al , ).…”