ClinVar

In 2 unrelated female patients of Kurdish ethnicity with late infantile neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Steinfeld et al. (2002) identified a homozygous A-to-G transition at nucleotide 857 in exon 7 of the TPP1 gene. The mutation resulted in an asn286-to-ser (N286S) substitution that altered 1 of 5 N-glycosylation sites in the TPP1 protein. Both patients had a more protracted clinical course compared with patients with typical disease progression.

By transient transfection analysis in human embryonic kidney cells, Tsiakas et al. (2004) found that TPP1 containing the N286S mutation was synthesized and sorted in the Golgi like wildtype TPP1, but it was expressed at a lower level and was enzymatically inactive. TPP1 with the N286 mutation had an apparent molecular mass 2 kD lower than that of wildtype TPP1, whereas deglycosylation of mutant and wildtype TPP1 led to proteins of the same size. Tsiakas et al. (2004) concluded that TPP1 with the N286S mutation lacks 1 oligosaccharide chain, resulting in enzymatic inactivation and possibly prelysosomal protein degradation.