Human Gene Discovery for Understanding Development of the Inner Ear and Hearing Loss

Bhonker, Yoni; Ushakov, Kathy; Avraham, Karen B.

doi:10.1016/b978-0-12-408088-1.00004-x

Cited by 1 publication

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“…Identification of genes involved in hearing provides unique opportunities to gain a deeper understanding of inner ear function. Functional studies of the proteins these genes encode, carried out in mouse models for human deafness, have greatly expanded our understanding of how this complex organ is formed and how it converts mechanical stimuli into electrical signals (Bhonker et al 2014; Richardson et al 2011). This approach has uncovered novel genes whose involvement in inner ear development would likely not have been predicted based on its known role in other tissues.…”

Section: Introductionmentioning

confidence: 99%

The GPSM2/LGN GoLoco motifs are essential for hearing

et al. 2015

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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. LgnΔC 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 LgnΔC 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.

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Section: Introductionmentioning

confidence: 99%