Cln1R151X mice contain the amino acid mutation R151X in exon 5 of the palmitoyl-protein thioesterase 1 (Ppt1) gene. CLN1 is a ubiquitous lysosomal enzyme responsible for removing palmitoyl groups from modified cysteine residues in polypeptides that have been targeted for degradation in the lysosome. Mutations in CLN1 most commonly lead to neuronal ceroid lipofuscinoses (NCL), autosomal recessive neurodegenerative disorder characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. These mutations most commonly lead to infantile NCL in which the patients exhibit microcephaly, seizures, motor abnormalities, ataxia and mental retardation leading to dementia, with death usually occurring by 8 to 13 years of age. Mutations can also lead to other clinical variants of NCL, such as variant forms of late-infantile NCL, juvenile NCL, and adult NCL.
In these mice, the R151X mutation introduces a nonsense mutation analogous to a Cln1 mutation commonly found patients with NCL. CLN1 proteins harboring the R151X mutation are targeted for degradation by the nonsense-mediated decay (NMD) pathway, leading to a significant decrease in CLN1 mRNA level and concurrent decrease in CLN1 enzyme activity in patient-derived lymphoblast cell lines. Tissues from heterozygous Cln1R151X mice showed a 1.42- to 1.85-fold decrease in Cln1 expression and tissues from homozygotes showed a 5.32- to 12.99-fold decrease in Cln1 expression. Mice display significant motor deficits by 3 months of age. They also have significant accumulation of autofluorescent storage material within the cortex, thalamus and hippocampus at 5 months of age, consistent with the neuropathological hallmarks of infantile NCL disease.
