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Author Notes:

Corresponding Author: Karen B. Avraham, karena@post.tau.ac.il

Acknowledgments: This work was performed in partial fulfillment of the requirements for a Ph.D. degree by Yoni Bhonker at the Sackler Faculty of Medicine, Tel Aviv University, Israel.

We wish to thank Megy Cemel and Michal Meir for their valuable contributions.

Conflict of Interest The authors declare that they have no conflict of interest.

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Research Funding:

This work was supported by the Human Frontier Science Program RGP0012/2012 (K. B. A., P. C., F. M., D. S.); National Institutes of Health (NIDCD) R01DC011835 (K. B. A., M. K.); I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation, Centers of Excellence in Gene Regulation in Complex Human Disease, Grant No. 41/11 (K. B. A.) and in Integrated Structural Cell Biology, Grant No. 1775/12 (E. T, M. L.); and a TEVA Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE) (Y. B.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Biotechnology & Applied Microbiology
  • Genetics & Heredity
  • PLANAR CELL POLARITY
  • CHUDLEY-MCCULLOUGH SYNDROME
  • TARGETED GENOMIC CAPTURE
  • AUDITORY HAIR-CELLS
  • PRIMARY CILIUM
  • PROTEIN
  • LGN
  • IDENTIFICATION
  • MECHANISMS
  • DIVISIONS
  • Hearing loss
  • Hair cell
  • Basal body
  • Primary Cilium
  • Auditory Brainstem Response

The GPSM2/LGN GoLoco motifs are essential for hearing

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Journal Title:

Mammalian Genome

Volume:

Volume 27, Number 1-2

Publisher:

, Pages 29-46

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The planar cell polarity (PCP) pathway is responsible for polarizing and orienting cochlear hair cells during development through movement of a primary cilium, the kinocilium. GPSM2/LGN, a mitotic spindle-orienting protein associated with deafness in humans, is a PCP effector involved in kinocilium migration. Here, we link human and mouse truncating mutations in the GPSM2/LGN gene, both leading to hearing loss. The human variant, p.(Trp326*), was identified by targeted genomic enrichment of genes associated with deafness, followed by massively parallel sequencing. Lgn ΔC mice, with a targeted deletion truncating the C-terminal GoLoco motifs, are profoundly deaf and show misorientation of the hair bundle and severe malformations in stereocilia shape that deteriorates over time. Full-length protein levels are greatly reduced in mutant mice, with upregulated mRNA levels. The truncated Lgn ΔC allele is translated in vitro, suggesting that mutant mice may have partially functioning Lgn. Gαi and aPKC, known to function in the same pathway as Lgn, are dependent on Lgn for proper localization. The polarization of core PCP proteins is not affected in Lgn mutants; however, Lgn and Gαi are misoriented in a PCP mutant, supporting the role of Lgn as a PCP effector. The kinocilium, previously shown to be dependent on Lgn for robust localization, is essential for proper localization of Lgn, as well as Gαi and aPKC, suggesting that cilium function plays a role in positioning of apical proteins. Taken together, our data provide a mechanism for the loss of hearing found in human patients with GPSM2/LGN variants.

Copyright information:

© 2015, Springer Science+Business Media New York.

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