The Asp620asn mutation in VPS35 is not a common cause of familial Parkinson's disease

Abstract

Genetic studies of familial Parkinson’s disease (PD) have revealed 5 major causative genes (SNCA, PRKN, DJ1, PINK1, LRRK2), which together account for less than 10% of inherited PD cases. 1 So far, the identification of genetic causes for Mendelian forms of PD has been based on classic linkage and Sanger sequence analysis. Very recently, however, the application of next-generation whole-exome sequencing technology to 2 large independent kindred with autosomal-dominant late-onset PD has led to the identification of VPS35, encoding the vacuolar protein sorting 35, as a novel disease-causing gene in 2 independent studies. 2,3 In the 2 analyzed families, the genetic determinant of the disease was the p.Asp620Asn mutation, suggesting that this might be a recurrent causative variant. The subsequent screening of about 6000 additional PD cases and 5000 controls, identified 6 more patients (5 with familial and 1 with sporadic PD) and no controls carrying the VPS35 p.Asp620Asn; in all 5 families the mutation cosegregated with the disease as an autosomal-dominant trait. 2,3 We observed that the 2 works do not report the rate of familial PD in the analyzed cohort. Therefore, to elucidate the relevance and frequency of the VPS35 p.Asp620Asn mutation in familial PD, we screened for this variant in an Italian PD cohort collected by the Biobank of the Parkinson Institute of Milan (http://www.parkinson.it/dnabank.html). Our population included 475 patients with familial PD (56% male; mean age of onset 54.17 6 10.9 years; mean disease duration 13.28 6 7.36 years), having at least 1 relative among their first-degree (284), second-degree (128), or third-degree (63) family members with a formal diagnosis of PD. The majority of cases (308) had a probable autosomal dominant inheritance of the disease. Major PD genes had been previously analyzed, and positive cases (13 LRRK2 ,1 2 PRKN, and 3 SNCA mutations) were not excluded. 4,5 Genotyping (99% success rate) was performed by the high-resolution melting technique 6 using a LightCycler480 (Roche, Basel, Switzerland) and the primer pair 5 0 -CAAC TAGAGGATGGTTGGTCCT-3 0 and 5 0 -AAAGTGCCAAT GATCAAGGTG-3 0 . The genomic DNA of an individual heterozygous for the p.Asp620Asn mutation (kindly provided