PPT1 – neuronal ceroid lipofuscinosis 1

PPT1 encodes palmitoyl-protein thioesterase 1, a lysosomal enzyme responsible for depalmitoylation of cysteine-modified proteins. Biallelic loss-of-function variants in PPT1 cause neuronal ceroid lipofuscinosis 1 (CLN1 disease), an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor regression, seizures, vision loss, and early death. The association between PPT1 and CLN1 is supported by extensive clinical, genetic, and functional data establishing a definitive gene–disease relationship.

Multiple independent case series have identified over 20 unrelated probands harboring homozygous or compound heterozygous PPT1 variants. Eight subjects from infantile NCL cohorts exhibited novel missense and truncating mutations, including c.451C>T (p.Arg151Ter), segregating in two families (PMID:10649502). A study of 12 Indian patients confirmed PPT1 deficiency in individuals presenting with epilepsy, visual impairment, and cerebral atrophy, uncovering both known (p.Val181Met) and novel (p.Cys45Arg, p.Pro238Leu) variants (PMID:30541466).

Segregation analysis in familial cases demonstrates co-segregation of PPT1 pathogenic alleles with CLN1 phenotypes, supporting recessive inheritance. Homozygosity for the common R151X founder variant was confirmed in multiple pedigrees, with at least five affected relatives across two kindreds (PMID:10649502).

The PPT1 variant spectrum includes nonsense (e.g., c.451C>T (p.Arg151Ter)), frameshift (c.346_347del), splice-site, and missense alleles. Recurrent R151X accounts for a significant proportion of infantile cases, and private truncating variants are frequently observed, consistent with loss-of-function as the pathogenic mechanism.

Functional studies corroborate the genetic data: the crystal structure of PPT1 revealed an α/β-hydrolase fold with a catalytic Ser115–His289–Asp233 triad, explaining how missense mutations abolish activity (PMID:10781062). Ppt1 knockout mice develop autofluorescent storage material, seizures, and neurodegeneration, faithfully modeling human CLN1 disease (PMID:11717424).

Compassionate use of a blood–brain barrier–penetrating PPT1 enzyme fusion (AGT-194) in a 68-month-old boy reduced seizure frequency and stabilized neurologic decline over 26 months without adverse events, illustrating translational potential (PMID:36324638).

Key Take-home: PPT1 demonstrates a definitive, autosomal recessive association with CLN1 disease; genetic testing and emerging enzyme replacement therapies offer actionable diagnostic and therapeutic avenues.

References

• Molecular genetics and metabolism reports • 2022 • Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme. PMID:36324638
• Human mutation • 2000 • Identification of three novel mutations of the palmitoyl-protein thioesterase-1 (PPT1) gene in children with neuronal ceroid-lipofuscinosis. PMID:10649502
• BMC neurology • 2018 • Batten disease: biochemical and molecular characterization revealing novel PPT1 and TPP1 gene mutations in Indian patients. PMID:30541466
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. PMID:11717424
• 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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