The GPSM2/LGN GoLoco motifs are essential for hearing

Yoni Bhonker, Amal Abu-Rayyan, Kathy Ushakov, Liat Amir-Zilberstein, Shaked Shivatzki, Ofer Yizhar-Barnea, Tal Elkan-Miller, Einav Tayeb-Fligelman, Sun Myoung Kim, Meytal Landau, Moien Kanaan, Ping Chen, Fumio Matsuzaki, David Sprinzak, Karen B. Avraham*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)29-46
Number of pages18
JournalMammalian Genome
Issue number1-2
StatePublished - 1 Feb 2016


FundersFunder number
Centers of Excellence in Gene Regulation in Complex Human Disease41/11, 1775/12
Israeli National Network of Excellence in Neuroscience
National Institutes of Health
National Institute on Deafness and Other Communication DisordersR01DC011835
Teva Pharmaceutical Industries
Human Frontier Science ProgramRGP0012/2012
Israel Science Foundation


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