Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations

Abstract

ObjectiveTo describe the clinical and functional consequences of 1 novel and 1 previously reported truncating MT-ATP6 mutation.MethodsThree unrelated probands with mitochondrial encephalomyopathy harboring truncating MT-ATP6 mutations are reported. Transmitochondrial cybrid cell studies were used to confirm pathogenicity of 1 novel variant, and the effects of all 3 mutations on ATPase 6 and complex V structure and function were investigated.ResultsPatient 1 presented with adult-onset cerebellar ataxia, chronic kidney disease, and diabetes, whereas patient 2 had myoclonic epilepsy and cerebellar ataxia; both harbored the novel m.8782G>A; p.(Gly86*) mutation. Patient 3 exhibited cognitive decline, with posterior white matter abnormalities on brain MRI, and severely impaired renal function requiring transplantation. The m.8618dup; p.(Thr33Hisfs*32) mutation, previously associated with neurogenic muscle weakness, ataxia, and retinitis pigmentosa, was identified. All 3 probands demonstrated a broad range of heteroplasmy across different tissue types. Blue-native gel electrophoresis of cultured fibroblasts and skeletal muscle tissue confirmed multiple bands, suggestive of impaired complex V assembly. Microscale oxygraphy showed reduced basal respiration and adenosine triphosphate synthesis, while reactive oxygen species generation was increased. Transmitochondrial cybrid cell lines studies confirmed the deleterious effects of the novel m.8782 G>A; p.(Gly86*) mutation.ConclusionsWe expand the clinical and molecular spectrum of MT-ATP6-related mitochondrial disorders to include leukodystrophy, renal disease, and myoclonic epilepsy with cerebellar ataxia. Truncating MT-ATP6 mutations may exhibit highly variable mutant levels across different tissue types, an important consideration during genetic counseling.

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

“…The central disease entity associated with homoplasmic mtDNA mutations is Leber’s hereditary optic neuropathy (LHON) [ 8 ]. Mutations in the same gene can lead to different clinical presentation; for instance, mitochondrial phenotypes described in patients with MT-ATP6 mutations span from maternally inherited Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)[ 9 ], to Charcot–Marie–Tooth disease [ 10 ], late-onset hereditary spastic paraplegia-like disorder [ 11 ], and MERRF-like phenotype [ 12 ]. Rearrangements (single deletions or duplications) of mtDNA are responsible for sporadic progressive external ophthalmoplegia (PEO), Kearns–Sayre syndrome (KSS) [ 13 ], and Pearson’s syndrome [ 14 , 15 ].…”

Delayed diagnoses of mitochondrial cytopathies in patients presenting with end stage kidney disease: two case reports

“…Muscle histology revealed mild myopathic changes with no specific features of mitochondrial disease. Next generation sequencing of mtDNA extracted from blood leukocytes, cultured fibroblasts and skeletal muscle tissue confirmed the presence of the pathogenic m.8618dup in MT-ATP6 at 20, 45 and 65% mutant loads, respectively [15]. The mutation was detected in other maternal relatives, albeit at lower levels (Fig.…”

“…2 Family pedigree structure Case 2. Percentage heteroplasmy in muscle (M), fibroblasts (F), blood (B) and urine (U) are shown (adapted from [ 15 ])

Fig. 3 Timeline of events Case 2

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Murine cerebral organoids develop network of functional neurons and hippocampal brain region identity

“…Therefore, we expressed the mitochondrial markers as fold-change of the nuclear marker Lamin B, rather than to the total protein content per lane. The voltage-dependent anion-selective channel 1 (VDAC 1) protein, a mitochondrial channel of the outer mitochondrial membrane widely used as an indicator of mitochondrial mass ( Bugiardini et al., 2020 ), significantly increased in the organoids at different maturation times (from 1 ± 0.59 at 7d to 19.99 ± 1.52 at 32d; p < 0.0001) ( Figures 3 B and 3H). Mitochondria are mainly responsible for energy production through the OXPHOS process that is upregulated in mature neurons compared to NSCs ( Beckervordersandforth et al., 2017 ; Bifari et al., 2020 ; Lorenz et al., 2017 ; Martano et al., 2019 ; Zheng et al., 2016 ; Inak et al., 2021 ).…”