LRRK2

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It is now clear that genetic risk is important in the pathogenesis of Parkinson disease (PD). Initial studies focusing on families with clear mendelian inheritance led to the identification of five genes with a confirmed role in PD etiology: α-synuclein ( SCNA ; PARK1), parkin ( PRKN ; PARK2), PTEN-induced putative kinase 1 ( PINK1 ; PARK6), oncogene DJ-1 ( DJ-1 ; PARK7), and leucine-rich repeat kinase 2 ( LRRK2 ; PARK8). Mutations in three of these genes, SCNA , PINK1 , and DJ-1 , are rare causes of PD.1 However, the role of parkin in PD etiology has been greatly expanded. Mutations in parkin were thought initially to cause only early-onset, autosomal recessive PD.2 Further studies have shown that mutations in parkin can be found among individuals with adult-onset disease3 and suggest that heterozygous mutations in parkin might act as a susceptibility factor, increasing the risk of PD.4 LRRK2 seems likely to contribute to more typical, idiopathic PD. Mutations have been reported in patients of all ages. However, LRRK2 has posed major challenges for researchers. The most formidable is the size of the gene. LRRK2 includes 51 exons. As a result, thorough screening of this gene to identify novel mutations is costly and time-consuming. Three articles in this issue of Neurology have taken different approaches to this difficult problem. Two …