A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants

Abstract

BackgroundTwo recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.Methods and resultsWe performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.ConclusionsOur study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

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

“…There are about 50 cases of the D620N mutation mentioned in literature. The frequency has previously been estimated to be about 0.1 to 1% in patients with familial autosomal dominant PD [21], but may be rarer than that [17]. Of those patients only insufficient clinical data are available.…”

“…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.…”