A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy

Abstract

To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.A homoplasmic nonsense mutation m.8529G→A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNAWe describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes

“…The patient in that report had onset as an adolescent and also had neuropathy, ataxia and developmental delay 15. Mutations in mtDNA disorders are sometimes viewed as less severe than autosomal recessive nuclear gene mitochondrial disorders, but clearly that is not the case in patients ascertained with m.8528T→C mutations to date.…”

“…The m.8528T→C alteration is predicted to affect both mitochondrial genome-encoded complex V subunits. In addition, a pathogenic mutation affecting the same amino acid (tryptophan) at position 55 of the ATPase 8 subunit has been previously reported 15. Interestingly, the m.8528T→C mutation occurs in four different mitochondrial genetic backgrounds with haplogroups M, B, H, and A in patients 1 to 4 respectively (supplementary table 1, online).…”

Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation

“…The maternally inherited disorders of ATP synthase are caused by mtDNA mutations in MTATP6 2–4 or rarely in MTATP8 5 genes. Their clinical presentation ranges from mild disorders to NARP or Leigh syndrome (symmetrical necrotic lesions in basal ganglia and/or the brain stem) and typically depends on the level of mtDNA heteroplasmy.…”

Cellular and functional analysis of four mutations located in the mitochondrial ATPase6 gene

“…Apart from the nucleotides T8993 and T9176, which appear to be hot-spots for mutations, few additional changes have been described in the ATPase6 gene [De Meirleir et al, 1995;Moslemi et al, 2005]. More recently, the first mutation in the mitochondrial ATPase8 gene (G8529A; W55X) has been described [Jonckheere et al, 2008].…”