DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease

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art_OLGIATI_DNAJC6_Mutations_Associated_With_EarlyOnset_Parkinsons_Disease_2016.PDF (772.56 KB)
Citações na Scopus
132
Tipo de produção
article
Data de publicação
2016
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY-BLACKWELL
Autores
OLGIATI, Simone
QUADRI, Marialuisa
FANG, Mingyan
ROOD, Janneke P. M. A.
SAUTE, Jonas A.
BOUWKAMP, Christian G.
GRAAFLAND, Josja
MINNEBOO, Michelle
BREEDVELD, Guido J.
Citação
ANNALS OF NEUROLOGY, v.79, n.2, p.244-256, 2016
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
ObjectiveDNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age<11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within approximate to 10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). MethodsThe DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. ResultsWe identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. InterpretationOur findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. Ann Neurol 2016;79:244-256
Palavras-chave
URI
https://observatorio.fm.usp.br/handle/OPI/14071
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Coleções
Artigos e Materiais de Revistas Científicas - HC/Outros
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/45