DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Mutations in DNAJC6 have been previously identified in families with autosomal recessive juvenile parkinsonism.
• These cases presented with early onset, atypical symptoms, and rapid progression.

Purpose of the Study:

• To investigate the role of DNAJC6 mutations in early-onset Parkinson's disease (PD).
• To identify novel mutations in DNAJC6 associated with PD and characterize the associated phenotype.

Main Methods:

• Analyzed the DNAJC6 gene in 274 patients with early-onset PD.
• Utilized cosegregation analysis, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies.
• Assessed auxilin protein levels in patient fibroblasts.

Main Results:

• Identified two families with novel homozygous DNAJC6 mutations linked to PD.
• Patients exhibited decreased auxilin protein levels and symptoms consistent with early-onset PD.
• A sporadic case with noncoding DNAJC6 variants potentially affecting RNA splicing was also identified.

Conclusions:

• Established a novel form of hereditary early-onset PD associated with DNAJC6 mutations.
• Recommend screening DNAJC6 in early-onset PD patients with suspected autosomal recessive inheritance.
• These findings underscore the importance of synaptic vesicle endocytosis and trafficking in PD pathogenesis.