The pathophysiology underlying spiral ganglion cell defect-induced
deafness remains elusive. Using the whole exome sequencing approach, in combination with functional assays and a mouse disease model, we identified the potentially novel
deafness-causative
MAP1B gene encoding a highly conserved
microtubule-associated protein. Three novel heterozygous
MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of
nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families. Here, we show that
MAP1B is highly expressed in the spiral ganglion neurons in the mouse cochlea. Using otic sensory neuron-like cells, generated by pluripotent stem cells from patients carrying the
MAP1B mutation and control subject, we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of
MAP1B, which are involved in the microtubule stability and dynamics. Strikingly, otic sensory neuron-like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties. Dysfunctions of these derived otic sensory neuron-like cells were rescued by genetically correcting
MAP1B mutation using CRISPR/Cas9 technology. Involvement of
MAP1B in hearing was confirmed by audiometric evaluation of
Map1b heterozygous KO mice. These mutant mice displayed late-onset progressive
sensorineural hearing loss that was more pronounced in the high frequencies. The spiral ganglion neurons isolated from
Map1b mutant mice exhibited the deficient phosphorylation and disturbed dynamics of microtubules.
Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice. Therefore, our data demonstrate that dysfunctions of spiral ganglion neurons induced by
MAP1B deficiency caused
hearing loss.