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

Area of Science:

• Genetics
• Mitochondrial Biology
• Neurology

Background:

• Perrault syndrome (PS) is a rare autosomal-recessive disorder.
• It is characterized by sensorineural hearing loss, ovarian dysgenesis, and neurological impairment.
• Pathogenic variants in TWNK, encoding mitochondrial helicase Twinkle, disrupt mtDNA maintenance and cause a subset of PS cases.

Purpose of the Study:

• To generate the first mouse models for Perrault syndrome using patient-specific TWNK mutations.
• To establish a genetically precise in vivo platform for dissecting PS disease mechanisms.
• To evaluate targeted therapies for mitochondrial dysfunction and sensorineural hearing loss.

Main Methods:

• CRISPR/Cas9 gene editing was used to introduce patient-specific TWNK missense mutations (c.814G>A and c.1166C>T) into mice.
• Mutations were introduced in homozygous and compound heterozygous states.
• Phenotypic analysis included assessment of hearing loss, locomotor activity, neuropathy, growth, and molecular assays of mtDNA, ATP, and respiratory chain function.

Main Results:

• Mutant mice exhibited profound hearing loss, locomotor hypoactivity, and axonal peripheral neuropathy.
• Molecular assays showed reduced mtDNA copy number and ATP content in muscle and brain.
• Impaired respiratory-chain function was observed in mutant mice, recapitulating core features of human PS.

Conclusions:

• The generated mouse models accurately recapitulate key phenotypes of human Perrault syndrome.
• These models provide a valuable in vivo platform for understanding PS pathogenesis.
• The models will facilitate the evaluation of potential therapeutic strategies for PS and related mitochondrial disorders.