Autosomal dominant genes in PD

LRRK2.
A genetic locus initially described as associated with late-onset PD in a large Japanese kindred demonstrated association with late-onset autosomal-dominant PD in several additional families, and missense mutations in the LRRK2 gene were identified. Sequence analysis of the encoded enzymatic domains revealed an alteration within the activation loop of the kinase domain responsible for a
significant percentage of PD disease in many case populations studied. In general, common genetic variation in LRRK2 does not appear to contribute heavily to PD susceptibility, with the exception of some Asian populations, but in some populations, the missense mutations themselves account for more than one third of PD cases. Mutations that clearly segregate with disease in well described
families and are overrepresented in PD cases versus age-matched controls represent a fraction of described LRRK2 variants, and the difficulty in distinguishing benign versus pathogenic variants prevents resolution of the true frequency
of LRRK2 mutations in PD.

a-Syn. The first genetic cause for PD was described in a large Italian family that inherited early-onset PD in an autosomal dominant fashion. Subsequently, missense mutations in the a-syn gene were also identified in Greek, German, and
Spanish families, with missense mutations localized to the N-terminal half of the protein. As opposed to missense mutations in LRRK2, pathogenic missense mutations
in the a-syn gene seem confined to only a handful of PD cases worldwide. Again in contrast with LRRK2, genetic variation in the a-syn promoter and other regions of the gene appears to modify susceptibility to PD. The identification of genomic multiplications that include a-syn and are causative for PD solidifies the importance of a-syn dosage in PD. The main strength that suggests a critical involvement for a-syn in PD does not necessarily lie with human genetic studies; rather, a-syn represents the major protein component of the pathologic structures that define PD-associated lesions in affected regions of the brain.