title: DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability.
abstract: Familial parkinson's disease is both clinically and genetically heterogeneous. By mapping the disease locus with a lod score of 5.13 to a < 3.5 Mbp region at 1p31.3 in a consanguineous family and subsequent exome sequencing analysis, we identified homozygous truncating mutation p.Q734X in DNAJC6. Four members of the family were afflicted with juvenile parkinsonism that presented with mental retardation, pyramidal signs and epilepsy, as well as varying degrees of a progressive neurological disease. Recently a splicing mutation in the same gene was reported in two brothers with juvenile parkinsonism that was not L-Dopa responsive and not accompanied by pyramidal signs or mental retardation. Also, an 80-kb deletion that included DNAJC6 sequences was identified in a boy reported as having obesity, epilepsy and mental retardation but not any signs of parkinsonism. The phenotype of our study family resembles both of those families, which among themselves do not share any clinical features. Our findings further establish DNAJC6 as a juvenile parkinsonism gene, and expand the spectrums of the parkinsonism phenotype and DNAJC6 mutation. DNAJC6 encodes the neuronal co-chaperone auxilin. We found that its transcript is highly significantly more abundant in brain as compared to the non-neural tissues assayed.
authors.affiliation: Boğaziçi University, Department of Molecular Biology and Genetics, KP 301, Bebek, 34342 Istanbul, Turkey.
authors.forename: Çiğdem
authors.initials: Ç
authors.lastname: Köroğlu
authors.forename: Leyla
authors.initials: L
authors.lastname: Baysal
authors.forename: Murat
authors.initials: M
authors.lastname: Cetinkaya
authors.forename: Hatice
authors.initials: H
authors.lastname: Karasoy
authors.forename: Aslıhan
authors.initials: A
authors.lastname: Tolun
mesh_terms: D000293:Adolescent; D000328:Adult; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: C494652:DNAJC6 protein, human; D050956:HSP40 Heat-Shock Proteins