A consanguineous family of Syrian origin, consisting of two healthy parents and three adult children affected by a neurological disorder, were analysed by exome sequencing. The two parents were heterozygous and the three children homozygous for a single nucleotide mutation in the TPP2-gene, leading to a change of amino acid 28 from Cys to Gly. The gene encodes tripeptidyl-peptidase II (TPPII), a high-molecular weight exopeptidase. Cys-28 is not completely conserved between species, and even though it is fairly close to the catalytic Asp-44 in the primary sequence, it is presumed to be at the surface of the protein, and the potential effect of the amino acid change on enzyme activity cannot easily be predicted. The aim of this work was therefore to investigate the effect of the change on the activity and stability of TPPII, using a model system with murine TPPII. Thus, the TPP2-gene containing the mutation was created by site-directed mutagenesis, expressed in E. coli and the TPPII variant C28G purified. It was compared to wild-type (wt) TPPII, expressed and purified in an identical system. The C28G variant is active and shows the same kinetic characteristics as the wt-enzyme. However, it appears to be more sensitive to oxidative damage, since it is even more dependent on stabilization by dithiotreitol (DTT) than wt TPPII. Dissociation of the active complex as a result of oxidative damage could give rise to an inactive enzyme. TPPII has been implicated in antigen processing and recent publications have demonstrated that nonsense mutations in the TPP2-gene lead to autoimmune disorders. It is possible that autoimmunity plays a role also in this neurological disorder, and might explain why the missense mutation is causing this disorder