Otoferlin-Related Auditory Synaptopathy: In Vitro Analysis of Disease Mechanisms (A03)

• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Experimental Models for the Understanding of Nervous System Diseases ; Otolaryngology, Phoniatrics and Audiology ; Human Genetics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528760423

Auditory synaptopathy is an important disease mechanism of sensorineural hearing loss, most commonly arising from variants in otoferlin. Its detailed pathophysiology remains unclear due to lacking genetic and biophysical analysis on mRNA and protein levels. We will explore underappreciated effects of variants on splicing and apply a heterologous system to assess expression and purify stably expressing mutants to un-cover Ca2+-, phospholipid-, and protein-binding properties, as well as analyze membrane tethering and fusion. Structure analysis will capture native-like and detergent-stabilized otoferlin. We aim to arrive at a detailed understanding of human phenotypes caused by deleterious otoferlin variants.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1690: Disease Mechanisms and Functional Restoration of Sensory and Motor Systems
• Applicant Institution: Georg-August-Universität Göttingen
• Project Heads: Dr. Julia Preobraschenski; Privatdozentin Barbara Vona, Ph.D.