Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis

Abstract

Neuronal ceroid lipofuscinoses (NCL) represent a group of common progressive encephalopathies of children which have a global incidence of 1 in 12,500. These severe brain diseases are divided into three autosomal recessive subtypes, assigned to different chromosomal loci. The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years, and characteristic storage bodies are found in brain and other tissues at autopsy. The molecular pathogenesis underlying the selective loss of neurons of neocortical origin has remained unknown. Here we report the identification, by positional candidate methods, of defects in the palmitoyl-protein thioesterase gene in all 42 Finnish INCL patients and several non-Finnish patients. The most common mutation results in intracellular accumulation of the polypeptide and undetectable enzyme activity in the brain of patients.

The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis

“…Mutations in a gene encoding the novel hydrolytic enzyme palmitoyl protein thioesterase 1 (PPT1) are the underlying cause of INCL (2). The PPT1 gene was identified as a candidate for the disorder when it was mapped to chromosome 1p32, a region known to contain the defective gene in a group of Finnish patients (3).…”

Specific alterations in levels of mannose 6-phosphorylated glycoproteins in different neuronal ceroid lipofuscinoses

“…By linkage analysis and screening of positional candidates, the defective gene (CLN1) in infantile NCL (Santavuori-Haltia disease) has been identified as palmitoylprotein thioesterase (PPT1) [2], an enzyme involved in the removal of the lipid moiety from S-acylated proteins [3]. By using a biochemical approach, the defective gene (CLN2) in classical late-infantile NCL (LINCL ; Jansky-Bielschowsky disease) was identified as an unusual and previously unknown pepstatin-insensitive protease [4].…”

Rare Disease Genes—Lessons and Challenges

“…Again, some Finnish diseases exemplify this: The identification of the mutated gene for diastrophic dysplasia provided evidence of the exceptional sensitivity of cartilage cells to the relative lack of sulfate ions as compared to other cell types (Hästbacka et al 1994). Similarly, the finding that the causative gene for the lethal infantile brain disorder INCL encoded a palmitoyl protein thioesterase demonstrated for the first time that proper removal of palmitoyl residues from lipid-modified proteins is an absolute requirement for the normal development and maturation of neocortical neurons (Vesa et al 1995). INCL is characterized by the rapid death of cortical neurons, whereas neurons in lower parts of the CNS remain intact.…”