Objective: We aim to implicate novel genes/mutations using whole-exome sequencing (WES) in selected pedigrees.

Background: Mutations have been identified in only 30% of familial parkinsonism.

Methods: DNA from affected probands with a family history of early-onset (<45 ys at onset) recessive Parkinson’s disease (PD) were selected for WES. Mutational screening was performed in multiethnic familial probands with early-onset PD. Functional studies included gene and protein expression. When possible, brain imaging was reviewed and neuropathology performed.

Results: Null homozygous mutations in a HSP40/DNAJ gene were identified in 2 unrelated families: i) a nonsense mutation (c.187A>T, p.K63X) in a Saskatchewan family (famA); ii) a splicing mutation (c.79-2A>G, S26fs13X) in an Italian family (famB). Both mutations segregate with disease, and are absent in ethnically-matched controls and public databases.

Initial clinical findings in famA were reported (Mov Disord1997,12:453-6) and the proband (onset at 13) has since come to autopsy (at 74). FamB proband (onset at 32) has a similar negligible progression of motor symptoms over 30 ys (H&Y stage 1/5 nowadays), with mild executive (FAB 12.1/18) and visuo-spatial dysfunction. Her brother (onset at 51) had early and prominent psychiatric features (hallucinations, delusions) with mild nonprogressive parkinsonism. FamA and B probands had similar sustained symptomatic benefit on small dose of levodopa, showing intermittent mild dyskinesia. Dopaminergic dysfunction was subtle and non-progressive in both families. Neuropathology (famA) revealed no alpha-synuclein pathology and only some age-related Alzheimer’s disease changes. Considering the mild nonprogressive course of motor symptoms, clinical diagnosis of PD was challenged in both families: however, levodopa discontinuation led invariably to substantial worsening of symptoms.

Functional analyses showed that both mutations ablate the protein expression and might interfere with alpha-synuclein processing.

Conclusions: Loss of the HSP40/DNAJ protein, a Hsc70 interactor, is a rare cause of parkinsonism and the 3rd DNAJ protein genetically linked to parkinsonism. Notably, it seems to be related to a very slow neurodegenerative process. Little is known on the protein function, but it is abundant in the substantia nigra pars compacta and plays a critical role in its function.

References: Rajput A, Kishore A, Snow B, Bolton CF, Rajput AH. Dopa-responsive, nonprogressive juvenile parkinsonism: report of a case. Mov Disord. 1997 May;12(3):453-6.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-member-of-the-hsp40dnaj-family-is-a-novel-gene-for-early-onset-parkinsonism/