Frequency of the D620N Mutation in VPS35 in Parkinson Disease

Abstract

Objective: To evaluate the frequency and clinical spectrum of the recently identified p.D620N mutation in the VPS35 gene in Parkinson disease (PD) in an international sample. Design: Genetic analysis by DNA sequencing and detailed clinical and neuropsychiatric assessment as well as neuroimaging in mutation carriers. Setting: Tertiary referral centers in Germany, Serbia, Chile, and the United States. Patients: One thousand seven hundred seventy-four patients with PD. Main Outcome Measure: Frequency of the p.D620N mutation.Results: A single mutation carrier was identified. The mutation carrier was a 60-year-old German man who had tremor-dominant PD since the age of 45 years. Longitudinal follow-up over 13 years revealed a disease progression from Hoehn and Yahr stage 1 to 3. There was evidence of mild cognitive impairment on the Montreal Cognitive Assessment. No abnormalities were observed by multimodal neuroimaging. He had a family history consistent with autosomal dominant inheritance. An affected paternal aunt and 3 reportedly unaffected siblings were also found to be mutation carriers.Conclusion: VPS35 mutations are a rare cause of PD in different populations. The clinical phenotype may be indistinguishable from idiopathic PD with the possible exception of an earlier age at onset. Genetic analysis of the extended family revealed incomplete penetrance of the p.D620N mutation.

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].…”

Control of mitochondrial homeostasis by endocytic regulatory proteins

“…Exciting new studies implicate the VPS35 retromer subunit and the retromer complex in PD and mitochondrial fission, forging a novel connection between an endocytic regulatory complex and a non-endocytic organelle (Follett et al, 2014;Kumar et al, 2012;Sharma et al, 2012;Struhal et al, 2014;Tang et al, 2015;Vilarino-Guell et al, 2011;Zimprich et al, 2011). However, while the relationship between VPS35, mitochondrial dynamics and PD is now irrefutable, the precise mechanism(s) by which VPS35 influences mitochondrial morphology remain somewhat controversial.…”

“…Recent studies have identified an important role for the retromer cargo selection complex protein VPS35 in the regulation of mitochondrial homeostasis and PD (Kumar et al, 2012;Struhal et al, 2014;Vilarino-Guell et al, 2011;Wang et al, 2016a,b;Zimprich et al, 2011). One recently published mechanism suggests that VPS35 controls the transport of the ubiquitin ligase Mul1 to the mitochondrial membrane (Tang et al, 2015).…”

“…One exciting new area of research relates to recent studies pointing to a novel role for endocytic regulatory proteins in controlling mitochondrial dynamics. For example, VPS35, a member of the retromer cargo selection complex initially described for its role in recycling the mannose-6-phosphate receptor from endosomes back to the trans-Golgi network (Arighi et al, 2004), has been implicated as a key modulator of mitochondrial dynamics and one of only a handful of proteins that causes familial PD (Kumar et al, 2012;Vilarino-Guell et al, 2011;Zimprich et al, 2011). Indeed, the suppression of VPS35 expression in neonatal hippocampal neurons leads to a degenerative morphology with the generation of abnormal dendritic spines and swollen axons (Wang et al, 2012), and VPS35 expression is decreased in the substantia nigra of PD patients (MacLeod et al, 2013).…”