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Hum Mutat. 2019 Aug 9. doi: 10.1002/humu.23891. [Epub ahead of print]

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

Author information

1
Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
2
Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, Ohio, USA.
3
Department of Pediatrics at The Ohio State University, Columbus, Ohio, USA.
4
Division of Genetic and Genomic Medicine at Nationwide Children's Hospital, Columbus, Ohio, USA.
5
Laboratory of Molecular Genetics, CHU Montpellier, University of Montpellier, Montpellier, France.
6
IRCCS Materno Infantile Burlo Garofolo, Trieste, Italy.
7
Centre of Reference for Genetic Sensory diseases, CHU Montpellier, University of Montpellier, Montpellier, France.
8
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Verona, Italy.

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.

KEYWORDS:

Autosomal dominant non-syndromic hearing loss; PLS1; fimbrin; new gene; protein modelling

PMID:
31397523
DOI:
10.1002/humu.23891

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