Genetic variations in and genes: Biochemical and clinical consequences in Parkinson disease.

Variants in the and genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the gene encoding for the leucine-rich repeat kinase 2 enzyme. -associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, -associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of and pathways, with double mutant carriers showing a milder phenotype compared to -associated PD. This review compares and -associated PD, and highlights possible genotype-phenotype associations for and separately, based on biochemical consequences of single variants.