Deciphering the role of heterozygous mutations in genes associated with parkinsonism

Summary The association of six genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component. Of these six genes, LRRK2 (leucine-rich repeat kinase 2, or PARK8), parkin (PARK2), and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency. Insights from initial familial studies suggest that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive. However, screening of patient cohorts has revealed that up to 70% of people heterozygous for LRRK2 mutations are unaffected, and that more than 50% of patients with mutations in parkin or PINK1 have only a single heterozygous mutation. Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset Parkinsonʹs disease. We discuss the roles of heterozygous LRRK2 mutations and heterozygous parkin and PINK1 mutations in the development of parkinsonism, and propose an integrated aetiological model for this complex disease.