VPS35 mutation in Japanese patients with typical Parkinson's disease

Abstract

Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late-onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 mutations. We screened 7 reported nonsynonymous missense variants of VPS35, including p.D620N, known as potentially disease-associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high-resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no controls. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor-predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N substitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, especially autosomal dominant PD or tremor-predominant PD.

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

“…Recently, the p.D620N mutation in the VPS35 gene was identified as a novel cause of autosomal dominant lateonset PD by two research groups [212,213] and five subsequent studies have identified this mutation in PD patients [214][215][216][217]. Moreover, PD-associated defects in RAB7L1 or LRRK2 lead to a deficiency of the VPS35 component of the retromer complex [218].…”

VPS35-Linked Parkinson’s Disease Resembles the Idiopathic Disease: A Review of Clinical Trials

“…Depression seemed to be more common than cognitive impairment. Atypical motor features were not found [12][13][14][15][16][17][18].…”

“…A knock in mouse model suspects that Vps35 D620N allele is a partial-loss-of-function allele and causes an early deficit in dopamine release perhaps before the onset of neurodegeneration [5].…”

Parkinson's disease cluster: the wind of change

“…Cognitive deterioration seems to be rare in these patients. The protein seems to be involved in endosomal trafficking and recycling of synaptic vesicles, suggesting it may be impaired in this form of PD [14,26].…”