Non-syndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e. approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next-generation sequencing to identify causal variants in PLS1 (c.805G>A, p.(E269K); c.713G>T, p.(L238R) and c.383T>C, p.(F128S)) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia. In silico protein modelling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1-/- mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice. This article is protected by copyright. All rights reserved.

Mutations in PLS1, encoding fimbrin, cause autosomal dominant non-syndromic hearing loss

Dell'Orco, Daniele;
2019-01-01

Abstract

Non-syndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e. approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next-generation sequencing to identify causal variants in PLS1 (c.805G>A, p.(E269K); c.713G>T, p.(L238R) and c.383T>C, p.(F128S)) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia. In silico protein modelling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1-/- mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice. This article is protected by copyright. All rights reserved.
Autosomal dominant non-syndromic hearing loss; PLS1; fimbrin; new gene; protein modelling
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/998980
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