Loss of function and structural variants in the PRKRA synaptic gene link mild cognitive impairment and tinnitus
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BACKGROUND
Genetics underlying the co-occurrence of tinnitus and mild cognitive impairment (MCI) is unknown.
METHODS
Adults with chronic tinnitus from five European clinics participated in a randomized controlled trial (N=294). They underwent deep phenotyping and blood sampling for genome sequencing. A subset with MCI (N=75) were analyzed for gene burden and structural variations.
RESULTS
The PRKRA gene showed an enrichment of rare loss-of-function variants in 15% of MCI patients, associated with mild-to-moderate tinnitus. Cognitive performance was linked to tinnitus, but not hyperacusis or high frequency hearing loss (HFHL), in patients with MCI gene variants, especially PRKRA. This association was independent of the APOE ε4 genotype. Protein modeling indicated that mutant PACT ( PRKRA ) lacking the dsRBM3 domain bound PKR with increased affinity.
CONCLUSIONS
Rare mutations in PRKRA are linked to tinnitus and MCI, but not to HFHL or sound hypersensitivity, potentially through vertical pleiotropy in individuals with non-Alzheimer’s dementia.
