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Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss
Limei Cui, … , Ye Chen, Min-Xin Guan
Limei Cui, … , Ye Chen, Min-Xin Guan
Published December 3, 2020
Citation Information: JCI Insight. 2020;5(23):e136046. https://doi.org/10.1172/jci.insight.136046.
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Research Article Genetics Otology

Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss

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Abstract

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.

Authors

Limei Cui, Jing Zheng, Qiong Zhao, Jia-Rong Chen, Hanqing Liu, Guanghua Peng, Yue Wu, Chao Chen, Qiufen He, Haosong Shi, Shankai Yin, Rick A. Friedman, Ye Chen, Min-Xin Guan

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Figure 4

MAP1B p.1400S>G mutation altered axon elongation and microtubule stability in differentiated OSN-like cells.

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MAP1B p.1400S>G mutation altered axon elongation and microtubule stab...
(A and D) Representative pictures of developing axons were costained with phalloidin (green) and an antibody against acetylated tubulin (red). Scale bars: 50 μm. (B and E) All 3 different genotypes of OSN-like cells showed long neurites and were positive for anti-TUJ1 staining (green). Scale bars: 50 μm. n = 40, 50, and 48 OSN-like cells for MAP1B+/+, MAP1B+/–, and MAP1B+/c genotypes, respectively. (C and F) The differentiated OSN-like cells were treated with vinblastine and stained with TUJ1 (green). Scale bars: 50 μm. Nuclei were stained with DAPI (blue). Qualification of relative level of Ac-tubulin (D), relative neurite length (E), and relative density of TUJ1 (F) were shown. Data are mean ± SEM of triplicates. *P <0.05, **P <0.01, and ***P <0.001 by 1-way ANOVA followed unpaired Student’s t test.

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