The clinical phenotype associated with TPP2 variants seems to be due to a partial or complete loss-of-function mechanism with insufficient residual activity of the TPP2 enzyme. Most patients with a severe phenotype carried mutations predicted to result in premature termination and absence of the TPP2 protein, while in the four patients with a milder phenotype (“multiple sclerosis-like”) the variants were missense mutations.
Only one missense variant, p.Gly500Asp (located in the subtilase S8 domain) was associated with a severe phenotype.
TPP2