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Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by elevated lactate and bilateral symmetric lesions in the basal ganglia, thalamus, brainstem, and cerebral white matter on T2-weighted MRI. Clinical features often include ophthalmoplegia, optic atrophy, spastic paraparesis, and variable intellectual disability, reflecting mitochondrial oxidative phosphorylation defects (PMID:25995486, PMID:20598281).
Autosomal recessive inheritance of truncating variants in C12orf65 (HGNC:26784; MTRFR) has been implicated in Leigh syndrome. A pair of monozygotic twins from consanguineous parents harbored a homozygous nonsense mutation, c.346delG (p.Val116Ter), consistent with loss of C12orf65 function (PMID:25995486). A subsequent single patient case report identified a novel homozygous frameshift variant, c.207_220del (p.Pro70fs), reinforcing autosomal recessive segregation and phenotypic concordance (PMID:32478789).
Independent multi-patient studies identified four additional unrelated individuals with homozygous 1-bp deletions and duplications in C12orf65 (c.33dup, p.Pro12fs; c.96_99dup, p.Pro34fs; c.210del, p.Gly72fs; c.248del, p.Val83fs), each predicting a premature stop codon and recapitulating the Leigh syndrome phenotype (PMID:20598281). These findings total five probands from four families, demonstrating reproducible biallelic loss-of-function in unrelated pedigrees.
The spectrum of pathogenic C12orf65 variants in Leigh syndrome is dominated by frameshift and nonsense mutations that truncate the GGQ motif–containing protein. The recurrent c.346delG (p.Val116Ter) allele has also been reported in Charcot–Marie–Tooth disease type 6, underscoring phenotypic heterogeneity and potential modifier effects (PMID:25995486). No missense or deep-intronic variants have been implicated in this context to date.
Functional studies in patient fibroblasts revealed marked reduction in mitochondrial protein synthesis, decreased assembly and activity of respiratory complexes I and IV, and impaired oxidative phosphorylation. Blue native PAGE and enzymatic assays confirmed respiratory chain dysfunction attributable to loss of C12orf65–mediated peptidyl-tRNA hydrolysis, consistent with a loss-of-function mechanism (PMID:23188110).
Taken together, biallelic truncating mutations in C12orf65 cause autosomal recessive Leigh syndrome through a loss-of-function mechanism disrupting mitochondrial translation. These data support moderate clinical validity and provide actionable diagnostic markers for genetic testing. Key take-home: C12orf65 truncating variants define a clinically recognizable Leigh syndrome subtype amenable to molecular diagnosis.
Gene–Disease AssociationModerateFive probands from four unrelated families with biallelic loss-of-function C12orf65 mutations and consistent phenotype Genetic EvidenceModerateMultiple unrelated recessive families harboring truncating C12orf65 variants (five probands total) Functional EvidenceModeratePatient fibroblast studies show impaired mitochondrial translation and respiratory complex dysfunction |