PPT1 – Neuronal ceroid lipofuscinosis

Palmitoyl-protein thioesterase 1 (PPT1) is a lysosomal enzyme encoded by PPT1 (HGNC:9325) whose deficiency causes autosomal recessive neuronal ceroid lipofuscinosis (NCL) (Gene Symbol; Disease Name). Affected individuals present in infancy or early childhood with progressive visual loss, seizures, motor and cognitive decline, and premature death.

Extensive genetic data support a definitive gene–disease relationship. Over 120 probands from >100 unrelated families worldwide have been reported with biallelic PPT1 variants, including 15 Finnish families demonstrating linkage to 1p32 (PMID:1672288) and 29 U.S. subjects with PPT1 deficiency (PMID:10191107). Variants span nonsense (e.g., c.451C>T (p.Arg151Ter)), frameshift, splice, and missense alleles that segregate recessively with infantile, late-infantile, and juvenile NCL phenotypes (PMID:9425237).

Inheritance is strictly autosomal recessive. Recurrent alleles, such as c.451C>T (p.Arg151Ter), account for 40–52% of disease-causing alleles in several populations. Segregation across at least 9 additional affected relatives has been documented in variant juvenile NCL families with granular osmiophilic deposits (PMID:9425237).

Functional studies corroborate pathogenicity. The crystal structure of PPT1 reveals an α/β-hydrolase fold with a Ser115–His289–Asp233 catalytic triad, explaining the impact of missense alleles (PMID:10781062). Patient cells exhibit markedly reduced PPT1 activity and lysosomal storage, which can be rescued by stop-codon read-through drugs (gentamicin, PTC124) (PMID:21704547). The Cln1(R151X) mouse model faithfully reproduces human molecular, histological, and behavioral features and shows increased PPT1 activity and partial phenotypic rescue with ataluren (PTC124) (PMID:25205113).

No significant conflicting evidence has been reported. Together, the volume of concordant genetic and experimental data establishes a definitive classification of PPT1 in autosomal recessive neuronal ceroid lipofuscinosis.

Key Take-home: PPT1 mutation and enzyme assays are essential for diagnosing NCL1, enable carrier screening, and guide emerging therapies targeting nonsense mutations.

References

• Genomics • 1991 • Infantile form of neuronal ceroid lipofuscinosis (CLN1) maps to the short arm of chromosome 1. PMID:1672288
• Molecular genetics and metabolism • 1999 • Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. PMID:10191107
• Human molecular genetics • 2015 • The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. PMID:25205113
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. PMID:10781062

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