title: A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism.
abstract: Parkinson disease is caused by neuronal loss in the substantia nigra which manifests by abnormality of movement, muscle tone, and postural stability. Several genes have been implicated in the pathogenesis of Parkinson disease, but the underlying molecular basis is still unknown for ∼70% of the patients. Using homozygosity mapping and whole exome sequencing we identified a deleterious mutation in DNAJC6 in two patients with juvenile parkinsonism. The mutation was associated with abnormal transcripts and marked reduced DNAJC6 mRNA level. DNAJC6 encodes the HSP40 Auxilin, a protein which is selectively expressed in neurons and confers specificity to the ATPase activity of its partner Hcs70 in clathrin uncoating. In Auxilin null mice it was previously shown that the abnormally increased retention of assembled clathrin on vesicles and in empty cages leads to impaired synaptic vesicle recycling and perturbed clathrin mediated endocytosis. Endocytosis function, studied by transferring uptake, was normal in fibroblasts from our patients, likely because of the presence of another J-domain containing partner which co-chaperones Hsc70-mediated uncoating activity in non-neuronal cells. The present report underscores the importance of the endocytic/lysosomal pathway in the pathogenesis of Parkinson disease and other forms of parkinsonism.
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
authors.forename: Yuval
authors.initials: Y
authors.lastname: Cinnamon
authors.forename: Asaf
authors.initials: A
authors.lastname: Ta-Shma
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.forename: Yang-In
authors.initials: YI
authors.lastname: Yim
authors.forename: Shamir
authors.initials: S
authors.lastname: Zenvirt
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Albert
authors.initials: A
authors.lastname: Taraboulos
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Lois E
authors.initials: LE
authors.lastname: Greene
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D000293:Adolescent; D034021:Auxilins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002966:Clathrin / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree
chemical_list: D034021:Auxilins; D002966:Clathrin; C494652:DNAJC6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones