Recessive variants in TWNK cause syndromic and non-syndromic post-synaptic auditory neuropathy through MtDNA...

Area of Science:

• Genetics
• Neuroscience
• Ophthalmology

Background:

• Recessive variants in the TWNK gene are linked to mitochondrial DNA (mtDNA) depletion syndromes.
• Hearing loss is a primary symptom, but clinical and pathological details remain unclear.
• Auditory neuropathy (AN) and Perrault syndrome are identified manifestations.

Purpose of the Study:

• To investigate the clinical and pathophysiological features of hearing loss caused by bi-allelic TWNK variants.
• To explore the role of TWNK in auditory pathways and its implications for cochlear implantation outcomes.
• To elucidate the molecular mechanisms underlying TWNK-associated auditory dysfunction.

Main Methods:

• Collected and analyzed five cases with bi-allelic TWNK variants from three Chinese families.
• Performed clinical evaluations, including audiological assessments and genetic analysis.
• Conducted immunolocalization studies in mouse inner ear and auditory cortex, and RT-PCR analysis of TWNK transcripts.

Main Results:

• Identified two cases of isolated auditory neuropathy and three cases of Perrault syndrome.
• Patients with cochlear implantation showed poor speech discrimination, indicating post-synaptic defects.
• Twinkle protein localization and variant effects on mtDNA binding were analyzed, revealing distinct pathogenic mechanisms.
• Differential expression of TWNK transcripts in the inner ear and brain was observed.

Conclusions:

• Bi-allelic TWNK variants cause both syndromic and non-syndromic auditory neuropathy.
• The molecular pathogenesis involves impaired mtDNA replication at post-synaptic auditory sites.
• Patients with TWNK-associated hearing loss are poor candidates for cochlear implantation; gene therapy may be a future treatment option.