{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:36:21Z","timestamp":1792424181844,"version":"4.5.0"},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,1,14]],"date-time":"2016-01-14T00:00:00Z","timestamp":1452729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100008383","name":"Stichting ParkinsonFonds","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008383","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Beijing Genomics Institute (BGI)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:italic>DNAJC6<\/jats:italic> mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age\u2009&lt;\u200911), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair\u2010bound within \u223c10 years from onset). Here, for the first time, we report <jats:italic>DNAJC6<\/jats:italic> mutations in early\u2010onset Parkinson's disease (PD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The <jats:italic>DNAJC6<\/jats:italic> open reading frame was analyzed in 274 patients with early\u2010onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole\u2010exome sequencing, and protein studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified two families with different novel homozygous <jats:italic>DNAJC6<\/jats:italic> mutations segregating with PD. In each family, the <jats:italic>DNAJC6<\/jats:italic> 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\u2010state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding <jats:italic>DNAJC6<\/jats:italic> variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early\u2010onset PD, had symptoms onset in the third\u2010to\u2010fifth 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\u2010onset PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings delineate a novel form of hereditary early\u2010onset PD. Screening of <jats:italic>DNAJC6<\/jats:italic> is warranted in all patients with early\u2010onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. 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