2. Academic Validation
  3. Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss

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

  • JCI Insight. 2020 Dec 3;5(23):e136046. doi: 10.1172/jci.insight.136046.
Limei Cui 1 2 3,  Jing Zheng 1,  Qiong Zhao 1 2 3,  Jia-Rong Chen 1 2,  Hanqing Liu 2,  Guanghua Peng 4,  Yue Wu 1,  Chao Chen 1 2,  Qiufen He 2,  Haosong Shi 5,  Shankai Yin 5,  Rick A Friedman 6,  Ye Chen 1 2 3,  Min-Xin Guan 1 2 3 6 7 8
Affiliations

Affiliations

  • 1 Division of Medical Genetics and Genomics, The Children's Hospital.
  • 2 Institute of Genetics and.
  • 3 Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4 Deaprtment of Otorhinolaryngology, the Affiliated Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China.
  • 5 Department of Otorhinolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 6 Division of Otolaryngology, University of California at San Diego School of Medicine, La Jolla California, USA.
  • 7 Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders, Hangzhou, Zhejiang, China.
  • 8 Joint Institute of Genetics and Genomic Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, Zhejiang, China.
PMID: 33268592 DOI: 10.1172/jci.insight.136046
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.

Keywords

Genetic diseases; Genetics; Molecular pathology; Otology; iPS cells.

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