DNAJC6 and SYNJ1: juvenile parkinsonism

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Simon Edvardson, Orly Elpeleg and colleagues (DNAJC6, with Suzanne Lesage and Alexis Brice); Çiğdem Köroğlu and Aslıhan Tolun (DNAJC6); Marialuisa Quadri, Vincenzo Bonifati and colleagues (SYNJ1); and, in the same issue of Human Mutation, Claudia Krebs and Coro Paisán-Ruiz with Pietro De Camilli and Zhenyu Yue (SYNJ1). The funders were not checked.

What happened

Edvardson's team used homozygosity mapping and exome sequencing (reading all protein-coding DNA) to find a harmful DNAJC6 mutation in two patients with juvenile parkinsonism; messenger RNA for the gene was sharply reduced (PLoS ONE 7:e36458, May 2012). DNAJC6 encodes auxilin, a neuron-specific helper that strips clathrin coats off vesicles. Köroğlu found another DNAJC6 mutation (p.Q734X) in a consanguineous family: four affected members had juvenile parkinsonism with intellectual disability, pyramidal signs and epilepsy (Parkinsonism Relat Disord 19:320–324, 2013). Quadri found homozygous SYNJ1 p.Arg258Gln in an Italian consanguineous family with parkinsonism, dystonia and cognitive decline, with poor levodopa response (Hum Mutat 34:1208–1215, 2013). SYNJ1 encodes synaptojanin 1, which also works in vesicle recycling. Krebs found the same SYNJ1 change, p.Arg258Gln, in an Iranian consanguineous family with early-onset parkinsonism and showed it impaired the enzyme's phosphatase activity in vitro (Hum Mutat 34:1200–1207, 2013). The two families are independent, so the SYNJ1 finding was replicated in the same issue.

Why it moved us toward a cure

Two independent genes with the same job, plus the retromer gene (landmark 36), showed that protein trafficking at the synapse is a pathway to dopamine-neuron death, beside synuclein and mitochondria (landmark 12, landmark 15). Quadri's team judged it a new Mendelian form, and the Krebs report supports that.

Outcome

Open. The conditions are rare and severe, the phenotype varies (Köroğlu's abstract notes an earlier 80-kb deletion that included DNAJC6 in a boy with obesity, epilepsy and intellectual disability but no parkinsonism), and no targeted therapy was found in these sources. The genes have become established causes of early-onset parkinsonism, but how this helps common Parkinson's is unproven.

Sources

• Edvardson et al., PLoS ONE 2012;7(5):e36458, DOI 10.1371/journal.pone.0036458
• Köroğlu et al., Parkinsonism Relat Disord 2013;19:320–324, DOI 10.1016/j.parkreldis.2012.11.006, PubMed 23211418
• Quadri et al., Hum Mutat 2013;34:1208–1215, DOI 10.1002/humu.22373, PubMed 23804577
• Krebs et al., Hum Mutat 2013;34:1200–1207, DOI 10.1002/humu.22372, PubMed 23804563
• Checked 19 Oct 2026: no erratum, comment or retraction is listed in Europe PMC for the four papers.
• Not yet verified: links between these genes and common Parkinson's; the funders; the origin of the Edvardson patients' families.