Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.

Abstract

Perrault syndrome (PS) is a rare autosomal-recessive disorder characterized by bilateral sensorineural hearing loss, ovarian dysgenesis in females, and variable neurological impairment. Pathogenic variants in TWNK, encoding the mitochondrial helicase Twinkle, disrupt mtDNA maintenance and underlie a subset of PS cases. Here, we generated the first mouse models carrying patient-specific TWNK missense mutations c.814G > A (p.Ala272Thr) and c.1166C > T (p.Ala389Val), both in homozygosity and compound heterozygosity, using CRISPR/Cas9 editing. Mutant mice exhibit profound hearing loss, locomotor hypoactivity, and axonal peripheral neuropathy, while overall growth remains normal. Molecular assays reveal a significant reduction in mtDNA copy number and ATP content in muscle and brain, accompanied by impaired respiratory-chain function. These phenotypes faithfully recapitulate core features of human PS, establishing a genetically precise in vivo platform to dissect disease mechanisms and to evaluate targeted therapies for mitochondrial dysfunction and sensorineural hearing loss.