PNPT1 – Leigh syndrome

Leigh syndrome is a severe infantile encephalopathy characterized by psychomotor regression, lactic acidosis, and characteristic bilateral basal ganglia lesions. The nuclear gene PNPT1 (polyribonucleotide nucleotidyltransferase 1) encodes the mitochondrial exoribonuclease PNPase, essential for mitochondrial RNA import and processing. Biallelic PNPT1 variants have been implicated in combined respiratory chain deficiencies leading to Leigh syndrome.

Genetic evidence includes a single patient presenting at one month of age with progressive neurologic decline and death by 2.4 years, harboring compound heterozygous PNPT1 variants c.406C>A (p.Arg136Ser) ([PMID:28645153]). In a follow-up multi-patient cohort of 64 Leigh syndrome cases, two unrelated families carried additional biallelic PNPT1 variants including a truncating allele c.574C>T (p.Arg192Ter) and a missense allele c.1519G>T (p.Ala507Ser) ([PMID:32020600]). Overall, 3 probands across 3 families support causality.

No multi-generational segregation beyond the index cases has been reported, consistent with autosomal recessive inheritance and a lack of affected heterozygotes. The variant spectrum in Leigh syndrome includes at least two missense and one nonsense variant affecting conserved residues and predicted to disrupt the active site of PNPase.

Functional studies demonstrate that expression of wild-type PNPT1 in patient myoblasts restores normal mitochondrial RNA processing and respiratory chain activity ([PMID:28645153]). Structural modeling predicts disruption of the PNPase active site by missense variants, and patient fibroblast rescue experiments confirm that PNPase deficiency leads to accumulation of unprocessed mitochondrial RNA, reduced oxidative phosphorylation complex activities, and cellular bioenergetic failure ([PMID:28645153]; [PMID:32020600]).

The pathogenic mechanism is loss of mitochondrial RNA processing due to PNPase deficiency, resulting in combined complex I–IV respiratory chain defects and Leigh syndrome. The concordance of genetic findings with functional rescue strongly supports a disease mechanism of autosomal recessive loss of function.

Key take-home: Biallelic PNPT1 loss-of-function variants cause Leigh syndrome by disrupting mitochondrial RNA maturation, offering diagnostic utility and guiding future therapeutic development.

References

• Human Molecular Genetics • 2017 • Defective mitochondrial RNA processing due to PNPT1 variants causes Leigh syndrome. PMID:28645153
• Clinical Genetics • 2020 • Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. PMID:32020600

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