DNAJC13 mutations in Parkinson disease

This finding seems to fit in with the pathways that are emerging as being important in idiopathic Parkinson's disease.

Carles Vilariño-Güell, Alex Rajput, Austen J. Milnerwood, Brinda Shah, Chelsea Szu-Tu, Joanne Trinh, Irene Yu, Mary Encarnacion, Lise N. Munsie, Lucia Tapia, Emil K. Gustavsson, Patrick Chou, Igor Tatarnikov, Daniel M. Evans, Frederick T. Pishotta, Mattia Volta, Dayne Beccano-Kelly, Christina Thompson, Michelle K. Lin, Holly E. Sherman, Heather J. Han, Bruce L. Guenther, Wyeth W. Wasserman, Virginie Bernard, Colin J. Ross, Silke Appel-Cresswell, A. Jon Stoessl, Christopher A. Robinson, Dennis W. Dickson, Owen A. Ross, Zbigniew K. Wszolek, Jan O. Aasly, Ruey-Meei Wu, Faycal Hentati, Rachel A. Gibson, Peter S. McPherson, Martine Girard, Michele Rajput, Ali H. Rajput and Matthew J. Farrer

Hum. Mol. Genet. (2013)

doi: 10.1093/hmg/ddt570

First published online: November 11, 2013

Abstract

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 were 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 2,928 patients and 2,676 control subjects from Canada, Norway, Taiwan, Tunisia and the United States.

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 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.