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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.

Original publication

DOI

10.1093/hmg/ddt570

Type

Journal article

Journal

Hum Mol Genet

Publication Date

01/04/2014

Volume

23

Pages

1794 - 1801

Keywords

Adult, Age of Onset, Aged, Base Sequence, Case-Control Studies, Cells, Cultured, Endocytosis, Endosomes, Family, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Lewy Bodies, Lewy Body Disease, Male, Middle Aged, Molecular Chaperones, Mutation, Parkinson Disease, Pedigree, Protein-Serine-Threonine Kinases, Sequence Alignment, Sequence Analysis, DNA, Vesicular Transport Proteins