A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease

Zimprich, Alexander; Benet‐Pagès, Anna; Struhal, Walter; Graf, Elisabeth; Eck, Sebastian; Offman, Marc N.; Haubenberger, Dietrich; Spielberger, Sabine; Schulte, Eva C.; Lichtner, Peter; Rossle, Shaila C.; Klopp, Norman; Wolf, Elisabeth; Seppi, Klaus; Pirker, Walter; Presslauer, Stefan; Mollenhauer, Brit; Katzenschlager, Regina; Foki, Thomas; Hotzy, Christoph; Reinthaler, Eva M.; Harutyunyan, Ashot S.; Královics, Róbert; Peters, Annette; Zimprich, Fritz; Brücke, Thomas; Poewe, Werner; Auff, Eduard; Trenkwalder, Claudia; Rost, Burkhard; Ransmayr, Gerhard; Winkelmann, Juliane; Meitinger, Thomas; Strom, Tim M.

doi:10.1016/j.ajhg.2011.06.008

Cited by 798 publications

(707 citation statements)

References 37 publications

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“…16 Over the last few years, many studies have shown the value of exome sequencing for gene discovery purposes in neurological disorders. [19][20][21][22][23] Next-generation sequencing technologies have also accelerated gene discovery in patients with dHMN, 9,24 CMT 25,26 or other inherited neuropathies. [27][28][29] More recently, the use of exome sequencing for diagnostic purposes in genetic disorders with a high degree of genetic heterogeneity such as CMT is being explored.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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Distal hereditary motor neuropathies (dHMNs) are a heterogenous group of genetic disorders with length-dependent degeneration of motor axons. Obtaining a genetic diagnosis in patients with dHMN remains challenging. We performed exome sequencing in a diagnostic setting in 12 patients with a clinical diagnosis of dHMN. Potential disease-causing variants in genes associated with dHMN and other forms of inherited neuropathies/motor neuron diseases were validated using Sequenom. The coverage in the genes studied was 495% with an average coverage of 450 times. In none of the patients a mutations was found in genes previously reported to be associated with dHMN. However, in 2/12 patients a recessive mutation in histidine triad nucleotide binding protein 1 (HINT1, recently discovered as a cause of axonal neuropathy with neuromyotonia) was identified. Our results demonstrate the diagnostic value of exome sequencing for patients with inherited neuropathies. The phenotypic spectrum of recessive mutations in HINT1 includes dHMN. HINT1 should be added to the list of genes to check for in dHMN.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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“…The importance of DNAJC13 function in endosomal trafficking is evident from several studies showing alterations in trafficking of well-known retromer cargos when its function is perturbed (13,20). The function of retromer itself is linked to PD through the observation that mutations in another retromer subunit, VPS35, can cause familial parkinsonism (6,7). Immunofluorescence and co-immunoprecipitation studies show endogenous VPS35 co-localizes with DNAJC13 in mouse primary cortical neuron cultures (Supplementary Material, Fig.…”

Section: Discussionmentioning

confidence: 99%

DNAJC13 mutations in Parkinson disease

Vilariño‐Güell

Rajput

Milnerwood

et al. 2013

Human Molecular Genetics

274

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A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case–control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch–German–Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.

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“…Two other genes [Leucine-rich repeat kinase 2 (LRRK2)/PARK8 and vacuolar protein sorting 35 ortholog (VPS35)] were since conclusively associated with autosomal dominant (AD) and four [parkin/PARK2, PTEN-induced kinase 1 (PINK1)/PARK6, DJ-1/PARK7, ATP13A2/PARK9] with early-onset autosomal recessive (AR) PD (Corti et al, 2011;Vilariño-Güell et al, 2011;Zimprich et al, 2011). Recently, mutations in eukaryotic translation initiation factor 4-gamma (EIF4G1)/PARK18 was reported as a probable cause of AD late-onset PD (Chartier-Harlin et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?

Lesage

Condroyer

Klebe

et al. 2012

Neurobiology of Aging

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Mutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene, encoding a component of the eIF4F translation initiation complex, were recently reported as a possible cause for the autosomal dominant form of Parkinson's disease (PD). Here, we describe the screening of all 31 EIF4G1 coding exons in a series of 251 index cases with autosomal dominant PD, mostly of French origin and in 236 European control subjects. We identified 12 rare coding variants (either nonsynonymous amino acid substitutions or in frame deletions/insertions), including 6 variants present only in cases and 3 in controls. Segregation was possible only for 1 variant (p.E462delInsGK) that was found in 2 affected siblings. In addition, we found 2 previously reported pathogenic variants in 2 isolated patients (p.G686C) and in a control subject (p.R1197W). These data do not support the pathogenicity of several EIF4G1 variants in PD, at least in the French population

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A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease

Cited by 798 publications

References 37 publications

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

DNAJC13 mutations in Parkinson disease

EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?

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