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LONP1 encodes a mitochondrial AAA+ protease essential for maintaining protein quality control and oxidative phosphorylation. While recessive LONP1 variants are established in CODAS syndrome, a classical mitochondrial presentation consistent with Leigh syndrome has now been reported. Whole-exome sequencing in one patient with congenital lactic acidosis and muscle weakness identified compound heterozygous c.1693T>C (p.Tyr565His) and c.2197G>A (p.Glu733Lys) variants in LONP1 (PMID:29518248). No additional affected relatives were available for segregation analysis. In vitro assays demonstrated that the p.Tyr565His mutant abolishes substrate binding and protease activity, and mixtures with p.Glu733Lys show severely depleted function consistent with a loss-of-function mechanism (PMID:29518248). The clinical features map to HP:0004902 (congenital lactic acidosis) and HP:0001324 (muscle weakness). These data support a limited but compelling genetic association and moderate functional evidence for recessive LONP1 loss-of-function as a cause of Leigh syndrome. Key take-home: LONP1 should be included in diagnostic panels for unexplained Leigh syndrome presentations.
Gene–Disease AssociationLimitedSingle proband with compound heterozygous variants and supportive functional data Genetic EvidenceLimitedOne case without segregation; two missense variants in trans Functional EvidenceModerateIn vitro assays show loss of substrate binding and protease activity consistent with disease mechanism |