Alternative Translation Initiation in PRKN Delays the Onset of Parkinson's Disease and Offers a Therapeutic Target.

PRKN exon 2 deletion → alternative translation initiation → partially functional truncated Parkin proteoform delaying disease onset

Homozygous carriers of a PRKN exon 2 deletion show a median age at onset of 39.5 years, significantly later than carriers of other PRKN variants. hiPSC-derived cellular models from an unaffected 86-year-old carrier revealed the mechanism: exon 2 deletion triggers internal translation initiation, producing a truncated Parkin proteoform (lacking aa 1-79) that retains partial function, explaining incomplete penetrance and late onset.

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This alternative translation initiation mechanism is novel for PRKN and has direct implications for genetic counseling: homozygous exon 2 carriers should not be considered equivalent to other biallelic carriers in terms of prognosis. The partially active truncated proteoform also constitutes a therapeutic lead to enhance residual proteoform expression.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Publication status: 1/1 → Total: 7/10