Submission Details

VPS35 was first reported in relation to autosomal-dominant Parkinson's disease in 2011 (Vilariño-Güell et al., PMID: 21763482; Zimprich et al., PMID: 21763483). Parkinson's disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine producing neurons in the substantia nigra, and Lewy bodies in the substantia nigra and locus coeruleus are found in most cases. Signs and symptoms include tremor which is most pronounced during rest, muscle rigidity, slowing of voluntary movements (bradykinesia), and a tendency to fall back (postural instability). One clearly pathogenic missense variant (p.Asp620Asn) has been reported in more than 60 patients by different authors/groups from different ethnicities (Struhal et al., PMID:24557499; Trinh et al., PMID: 30357936, https://www.mdsgene.org/). Five of these publications are included in this curation. The additional evidence from the literature was not included in this curation because the maximum score for genetic evidence (12 pts.) has been reached. Several reports also found additional missense variants in VPS35 such as p.Pro316Ser, p.Arg524Trp, or p.Leu774Met that might be causative for Parkinson's disease, however, these variants have not been included in the curation of VPS35 due to limited evidence. The disease follows an autosomal dominant mode of inheritance with age-dependent penetrance (Trinh et al., PMID: 25330418; https://www.mdsgene.org/). The midbrain and braintem neuropathology of VPS35 p.Asp620Asn has yet to be reported, but examination of the cortex and basal ganglia in one case (46 years at onset with 8 years disease duration) was normal with no neuronal loss, gliosis, senile plaques, neurofibrillary tangles or intraneuronal inclusions, and immunostaining for α-synuclein was negative (Wider et al., PMID: 18342564). The encoded protein, Vacuolar Protein Sorting 35, is a critical component of the retromer cargo-recognition complex that is composed of VPS35, VPS26 and VPS29. Any perturbation to wild-type retromer subunit stoichiometry (VPS35:VPS26:VPS29) is neurotoxic (Munsie et al., PMID: 25416282). The retromer recycles membrane-associated proteins between endosomes and the trans-Golgi network or the plasma membrane (Seaman. PMID: 33526371). The VPS35 gene-disease association is supported by recurrent experimental evidence including in-vitro functional assays and knock-in mice models for the p.Asp620Asn change. The proposed mechanism of pathogenicity is gain-of-function (GOF, Tsika et al., PMID: 24740878). It has been shown that VPS35 acts upstream of LRRK2, another gene where mutations cause autosomal dominant Parkinson's disease. VPS35 plays a role in regulating LRRK2 kinase catalytic activity with the p.Asp620Asn mutation increasing autophosphorylation of LRRK2 and phosphorylation of targets of LRRK2´s kinase activity (Mir et al., PMID: 29743203; Kadgien et al., PMID: 34530877). Non-human cell lines overexpressing hVPS35:Asp620Asn and induced pluripotent stem cell (iPSC)-derived neurons from patients with the p.Asp620Asn mutation show changes related to altered endosomal and retromer function (Follet et al., PMID: 24152121; Zavodszky et al., PMID: 24819384; Bono et al., PMID: 33032646; Hanss et al., PMID: 33142012; Cui et al., PMID: 33347683). Specifically, VPS35 p.Asp620Asn disrupts interactions with the Wiskott-Aldrich syndrome and SCAR homolog (WASH) complex, likely via FAM21 (McGough et al., PMID: 24980502; Zavodszky et al., PMID: 24819384). Further investigations in mutant knock-in animal models demonstrated altered dopamine metabolism, loss of dopaminergic neurons, and motor deficits in aged animals (Wang et al., PMID: 25288323; Cataldi et al., PMID: 30155515; Chen et al., PMID: 30842285; Niu et al. PMID: 33745227). Plasma membrane recycling of the dopamine transporter is mediated by retromer (Wu et al., PMID: 28847807) and impaired in Vps35 p.Asp620Asn knock-in mice (Cataldi et al., PMID: 30155515). The neuropathology observed in aged knock-in mice remains controversial as tauopathy (Chen et al., PMID: 30842285) or alpha-synucleinopathy (Niu et al. PMID: 33745227) are reported by different investigators in an identical strain. In summary, VPS35 definitively causes autosomal-dominant Parkinson's disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.