Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss

Anna Morgan, Daniel C. Koboldt, Elizabeth S. Barrie, Erin R. Crist, Gema García García, Massimo Mezzavilla, Flavio Faletra, Theresa Mihalic Mosher, Richard K. Wilson, Catherine Blanchet, Kandamurugu Manickam, Anne Francoise Roux, Paolo Gasparini, Daniele Dell’Orco, Giorgia Girotto

Research output: Contribution to journalArticlepeer-review

Abstract

Nonsyndromic 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 modeling 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.

Original languageEnglish
Pages (from-to)2286-2295
Number of pages10
JournalHuman Mutation
Volume40
Issue number12
DOIs
Publication statusPublished - Dec 1 2019

Keywords

  • autosomal dominant nonsyndromic hearing loss
  • fimbrin
  • new gene
  • PLS1
  • protein modeling

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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