MT-ATP6 – Leigh syndrome

Maternal inheritance; early‐onset subacute necrotizing encephalomyelopathy

MT-ATP6 encodes subunit a of the mitochondrial ATP synthase (complex V). Pathogenic variants in MT-ATP6 lead to defective ATP production and are a well‐established cause of Leigh syndrome, a progressive neurodegenerative disorder with characteristic bilateral basal ganglia and brainstem lesions. MT-ATP6-related Leigh syndrome is maternally inherited via heteroplasmic or homoplasmic mtDNA and shows variable penetrance depending on mutant load.

1 Assess Clinical Validity

Overall, the MT-ATP6–Leigh syndrome association is classified as Strong in ClinGen terms. Over 218 patients across more than 100 unrelated maternally inherited pedigrees harbor pathogenic MT-ATP6 variants, predominantly at nucleotide 8993, with consistent segregation of high‐level heteroplasmy in affected individuals and lower heteroplasmy or absence in asymptomatic maternal relatives ([PMID:30763462]). Functional studies in patient cells and model organisms concordantly demonstrate ATP synthase impairment.

2 Summarise Genetic Evidence

Inheritance is exclusively mitochondrial (maternal). Segregation analyses across >50 families document transmission of MT-ATP6 variants from affected mothers to multiple offspring. Case series report at least 2 additional affected relatives in individual pedigrees with confirmed high heteroplasmy levels ([PMID:8726250]). The variant spectrum includes missense changes (m.8993T>G/C, m.9176T>C/G), microdeletions (9205ΔTA), and truncating mutations; recurrent m.8993T>G and m.8993T>C mutations are observed in diverse populations. Heteroplasmy thresholds of >90% correlate with severe Leigh phenotype, whereas lower levels (<70%) may present with NARP or asymptomatic carriers.

3 Summarise Functional / Experimental Evidence

Pathogenic mechanism is predominantly impaired coupling between proton translocation and ATP synthesis, leading to deficient ATP production and elevated membrane potential. Patient fibroblasts and transmitochondrial cybrids with m.8993T>G/C mutations exhibit 60–70% reduced ATP synthesis and abnormal complex V assembly ([PMID:15265003], [PMID:17121862]). Yeast models of T9185C and T9191C variants recapitulate assembly defects and quantify ATP synthesis deficits proportional to mutation severity. Rescue experiments via allotopic expression of MT-ATP6 restore ATP synthase function and cellular respiration.

4 Address Conflicting Evidence

Asymptomatic maternal carriers with intermediate heteroplasmy levels (40–70%) underscore a threshold effect and variable expressivity. Some studies report minimal functional deficits in cell types with lower mutant loads, indicating tissue‐specific heteroplasmy dynamics and compensatory mechanisms.

5 Integrate & Conclude

MT-ATP6 variants cause a mitochondrial bioenergetic defect underpinning Leigh syndrome. Strong genetic evidence, maternal segregation, and concordant functional data support a definitive role for complex V impairment in disease pathogenesis. Heteroplasmy quantification guides diagnosis and risk assessment. Key take-home: MT-ATP6 testing with heteroplasmy analysis is critical for early diagnosis and management of Leigh syndrome.

References

• Human Mutation | 2019 | MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases PMID:30763462
• American Journal of Human Genetics | 1992 | Heteroplasmic mtDNA mutation at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high PMID:1550128
• Pediatric Research | 1996 | Clinical heterogeneity associated with the mitochondrial DNA T8993C point mutation PMID:8726250
• Biochemical Journal | 2004 | Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 2 bp microdeletion of TA at positions 9205 and 9206 PMID:15265003
• Journal of Biological Chemistry | 2007 | ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization PMID:17121862
• Molecular Genetics & Metabolism | 2018 | Novel insights into the functional metabolic impact of an apparent de novo m.8993T>G variant in the MT-ATP6 gene associated with maternally inherited form of Leigh Syndrome PMID:29602698

Evidence Based Scoring (AI generated)