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preLekára.sk / Odborné časopisy / PLOS Genetics / 2015 - 3

HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice

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The most frequent sensory disorder worldwide is hearing impairment. It impacts over 5% of the world population (360 million persons), and is characterized by extreme genetic heterogeneity. Over 80 genes have been implicated in isolated (also referred to as ‘non-syndromic’) hearing loss, and abundant evidence supports the existence of many more ‘deafness-causing’ genes. In this study, we used a sequential screening strategy to first exclude causal mutations in known deafness-causing genes in a family segregating autosomal dominant non-syndromic hearing loss. We next turned to whole exome sequencing and identified a single variant—p.Arg185Pro in HOMER2—that segregated with the phenotype in the extended family. To validate the pathological significance of this mutation, we studied two animal models. In zebrafish, we overexpressed mutant HOMER2 and observed inner ear defects; and in mice we documented robust expression in stereocilia of cochlear hair cells and demonstrated that its absence causes early-onset progressive deafness. Our data offer novel insights into gene pathways essential for normal auditory function and the maintenance of cochlear hair cells.

Vyšlo v časopise: HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005137
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005137

Souhrn

The most frequent sensory disorder worldwide is hearing impairment. It impacts over 5% of the world population (360 million persons), and is characterized by extreme genetic heterogeneity. Over 80 genes have been implicated in isolated (also referred to as ‘non-syndromic’) hearing loss, and abundant evidence supports the existence of many more ‘deafness-causing’ genes. In this study, we used a sequential screening strategy to first exclude causal mutations in known deafness-causing genes in a family segregating autosomal dominant non-syndromic hearing loss. We next turned to whole exome sequencing and identified a single variant—p.Arg185Pro in HOMER2—that segregated with the phenotype in the extended family. To validate the pathological significance of this mutation, we studied two animal models. In zebrafish, we overexpressed mutant HOMER2 and observed inner ear defects; and in mice we documented robust expression in stereocilia of cochlear hair cells and demonstrated that its absence causes early-onset progressive deafness. Our data offer novel insights into gene pathways essential for normal auditory function and the maintenance of cochlear hair cells.

Zdroje

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