Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits [published erratum appears in Hum Mol Genet 1998 Apr;7(4):765]

Abstract

A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT ; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in vJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.

Identification of three novel mutations of the palmitoyl-protein thioesterase-1 (PPT1) gene in children with neuronal ceroid-lipofuscinosis

“…Deficiency in PPT1, a lysosomal enzyme, causes the accumulation of proteolipid storage material that has the ultrastructural appearance of granular osmiophilic deposits (GROD) in brain and other tissues (Haltia et al 1973). Formerly believed to be rare outside of Finland, PPT1 deficiency has been described in the United States and in Europe, where a total of 22 mutations have been reported (Das et al 1998;Mitchison et al 1998;Santorelli et al 1998;Vesa et al 1995). Here, we have analyzed eight unrelated PPT1-deficient subjects and identified three novel mutations in the PPT1 gene (GenBank NM000310).…”

Mutations in palmitoyl-protein thioesterase 1 alter exocytosis and endocytosis at synapses in Drosophila larvae

“…6 The infantile onset form of the disease (INCL) is one of the more severe forms, with symptoms such as blindness, ataxia, and mental decline beginning to appear by 6-12 mo of age. [7][8][9] Mutations in the soluble lysosomal enzyme Ppt1 are the underlying molecular cause of the disease, but it is still unclear why the loss of this ubiquitously expressed protein produces a very specific neurodegenerative phenotype. 4 The disease phenotype provides further support that efficient Infantile-onset neuronal ceroid lipofuscinosis (INCL) is a severe pediatric neurodegenerative disorder produced by mutations in the gene encoding palmitoyl-protein thioesterase 1 (Ppt1).…”

Genetic Modifiers of Drosophila Palmitoyl–Protein Thioesterase 1-Induced Degeneration

“…Infantile onset NCL (INCL), produced by loss of palmitoyl-protein thioesterase 1 (PPT1) function, is the earliest and most severe form of NCL with symptoms appearing as early as 6 months of age and culminating with death between 24 months and 53 years of age (Wisniewski 2005). Although primarily associated with INCL, mutations in Ppt1 can also give rise to late-infantile, juvenile, and adult-onset NCL (Mitchison et al 1998;van Diggelen et al 2001). This variation in age of onset is likely related to residual enzyme activity produced by the specific mutation(s) a patient carries (Wisniewski 2005).…”