Identification of VPS35 mutations replicated in French families with Parkinson disease

Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Toulouse, France.
Neurology (Impact Factor: 8.29). 04/2012; 78(18):1449-50. DOI: 10.1212/WNL.0b013e318253d5f2
Source: PubMed


Since Next Generation DNA Sequencing (NGS) was first used to study Miller syndrome,(1) exome capture and sequencing have uncovered novel causative mutations in an increasing number of genetic disorders, including neurodegenerative diseases.(2-4) Two independent groups recently found the same heterozygous missense mutation, D620N (c.1858G>A), in the vacuolar protein sorting 35 ortholog gene (VPS35) associated with autosomal dominant late-onset Parkinson disease (PD).(5,6) It segregated with the disease in 2 large families of Swiss(5) and Austrian origin.(6) Further screening by both groups detected the mutation in 8 families from Austria, Switzerland, the United States, Tunisia, and Israel, and 2 rare, potentially pathogenic variants (P316S, R524W) in 1 family in each of the studies. We screened the VPS35 gene in a large sample of PD families with autosomal dominant inheritance, mostly from France, and analyzed the associated phenotypes.

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    • "To further highlight the relevance of our data to PD, the human homologue of Vps35, VPS35, has recently been identified as the latest confirmed causative gene of the typical late onset PD, with c.1858 > A (p.Asp620Asn) being the most common VPS35 mutation [36,37]. This finding has been replicated by several independent analyses [38-42]. However, the mechanism by which VPS35 is involved in PD pathogenesis is entirely unknown. "
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    ABSTRACT: Background Parkinson’s disease (PD) is the most common movement neurodegenerative movement disorder. An incomplete understanding of the molecular pathways involved in its pathogenesis impedes the development of effective disease-modifying treatments. To address this gap, we have previously generated a Drosophila model of PD that overexpresses PD pathogenic mutant form of the second most common causative gene of PD, Leucine-Rich Repeat Kinase 2 (LRRK2). Findings We employed this model in a genetic modifier screen and identified a gene that encodes for a core subunit of retromer – a complex essential for the sorting and recycling of specific cargo proteins from endosomes to the trans-Golgi network and cell surface. We present evidence that overexpression of the Vps35 or Vps26 component of the cargo-recognition subunit of the retromer complex ameliorates the pathogenic mutant LRRK2 eye phenotype. Furthermore, overexpression of Vps35 or Vps26 significantly protects from the locomotor deficits observed in mutant LRRK2 flies, as assessed by the negative geotaxis assay, and rescues their shortened lifespan. Strikingly, overexpressing Vps35 alone protects from toxicity of rotenone, a neurotoxin commonly used to model parkinsonism, both in terms of lifespan and locomotor activity of the flies, and this protection is sustained and even augmented in the presence of mutant LRRK2. Finally, we demonstrate that knocking down expression of Vps35 in dopaminergic neurons causes a significant locomotor impairment. Conclusions From these results we conclude that LRRK2 plays a role in the retromer pathway and that this pathway is involved in PD pathogenesis.
    Full-text · Article · Jun 2014 · Molecular Neurodegeneration
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    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. © 2012 Movement Disorder Society.
    Full-text · Article · Sep 2012 · Movement Disorders
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    ABSTRACT: Background Two 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 results We 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. Conclusions Our 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.
    Full-text · Article · Nov 2012 · Journal of Medical Genetics
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