DNAJC6 – young-onset Parkinson disease

DNAJC6 encodes the neuronal co-chaperone auxilin essential for clathrin-mediated endocytosis. Biallelic loss-of-function (LOF) mutations in DNAJC6 cause autosomal recessive early-onset Parkinson disease (PARK19). Model organisms and cell systems recapitulate dopaminergic neurodegeneration, linking DNAJC6 paucity to α-synuclein accumulation and lysosomal dysfunction.

In two unrelated families, four individuals with juvenile parkinsonism harbored novel homozygous splice-site and frameshift mutations in DNAJC6, which segregated with disease and mapped to runs of homozygosity within linkage peaks (PMID:26528954). A sporadic patient carried compound heterozygous noncoding variants likely affecting RNA splicing (PMID:26528954), and patient fibroblasts exhibited severely reduced auxilin levels.

Population screens in 664 Chinese early-onset PD patients identified a nominally significant heterozygous p.Asn526Ser variant in DNAJC6 (PMID:32662538), while a study of 117 Han Chinese cases found no known LOF alleles but reported a conserved heterozygous c.2798T>C (p.Val933Ala) (PMID:27687717), suggesting allelic heterogeneity and low overall prevalence.

The variant spectrum in recessive PARK19 includes canonical LOF alleles such as splice-site mutations (c.194-1G>A, c.666+1G>A) and a nonsense variant c.454C>T (p.Arg152Ter). No founder mutations or carrier frequencies have been established to date.

Mechanistic studies demonstrate that DNAJC6 LOF induces auxilin paucity, impairing clathrin uncoating, reducing lysosomal cathepsin D, and leading to pathological α-synuclein accumulation, ER stress, mitochondrial dysfunction, and dopaminergic cell death. shRNA-mediated knockdown in SH-SY5Y neurons was rescued by α-synuclein or cathepsin D suppression, whereas PARK19 mutants Q789X and R927G failed to restore neuroprotection (PMID:38928416).

Human midbrain-like organoids harboring DNAJC6 LOF mutations recapitulated mDA neuron degeneration, α-synuclein pathology, altered firing rates, mitochondrial and lysosomal deficits, and disrupted WNT-LMX1A signaling (PMID:33597231). A Drosophila knock-in model of auxilin mutation exhibited synaptic dysfunction, neurodegeneration, and lipid metabolism defects that were rescued by Synaptojanin-1 overexpression (PMID:36739293).

Despite negative or nominal findings in population cohorts, there are no published refutations of the DNAJC6–young-onset Parkinson disease relationship. The aggregate data support a Moderate ClinGen classification with robust functional concordance. Key take-home: biallelic LOF variants in DNAJC6 warrant inclusion in diagnostic panels for autosomal recessive early-onset Parkinson disease.

References

• Annals of neurology • 2016 • DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease. PMID:26528954
• Neuroscience letters • 2016 • DNAJC6 mutations are not common causes of early onset Parkinson's disease in Chinese Han population. PMID:27687717
• Movement disorders : official journal of the Movement Disorder Society • 2020 • Mutation Analysis of DNAJC Family for Early-Onset Parkinson's Disease in a Chinese Cohort. PMID:32662538
• International journal of molecular sciences • 2024 • Downregulation of Protease Cathepsin D and Upregulation of Pathologic α-Synuclein Mediate Paucity of DNAJC6-Induced Degeneration of Dopaminergic Neurons PMID:38928416
• Science advances • 2021 • Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations. PMID:33597231
• NPJ Parkinson's disease • 2023 • Parkinsonism mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1. PMID:36739293

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