Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Genetics Otology

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

  • Text
  • PDF
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

×

Figure 2

Generation of otic sensory neuron–like cells from patient-derived iPSCs.

Options: View larger image (or click on image) Download as PowerPoint
Generation of otic sensory neuron–like cells from patient-derived iPSCs....
(A) Schematic diagram illustrating the neuronal differentiation processing from iPSCs with 3 different genotypes. Cells were derived from married-in control (NB066–II-6) and hearing-impaired subject (NB066–II-4), and these underwent CRISPR/Cas9-based genetic correction, presented as MAP1B+/+, MAP1B+/–, and MAP1B+/c, respectively. (B) Phase contrast microscopy and AP staining of the iPSC colonies. Scale bars: 200 μm. (C) iPSCs were induced toward otic neuronal progenitors and stained for the markers PAX2 (red) and SOX2 (green). Nuclei were stained with DAPI (blue). Scale bars: 40 μm. (D) MAP1B, NEUROG1, NTRK2, and NTRK3 mRNA expression levels were analyzed using SYBR green real-time PCR and were normalized to β-actin mRNA expression. (E) Generations of otic neurons were confirmed by immunostaining with neuronal marker TUJ1 (green). Nuclei were stained with DAPI (blue). Scale bars: 50 μm. (F) TUJ1, NEUROG1, NTRK2, and NTRK3 mRNA expression levels were analyzed in differentiated OSN-like cells. Data are mean ± SEM of triplicates. *P < 0.05 and **P <0.01 by 1-way ANOVA followed unpaired Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts