Enrichment of LOVD-USHbases with 152 USH2A Genotypes Defines an Extensive Mutational Spectrum and Highlights Missense Hotspots

David Baux, Catherine Blanchet, Christian Hamel, Isabelle Meunier, Lise Larrieu, Valérie Faugère, Christel Vaché, Pierangela Castorina, Bernard Puech, Dominique Bonneau, Sue Malcolm, Mireille Claustres, Anne Françoise Roux

Research output: Contribution to journalArticlepeer-review


Alterations of USH2A, encoding usherin, are responsible for more than 70% of cases of Usher syndrome type II (USH2), a recessive disorder that combines moderate to severe hearing loss and retinal degeneration. The longest USH2A transcript encodes usherin isoform b, a 5,202-amino-acid transmembrane protein with an exceptionally large extracellular domain consisting notably of a Laminin N-terminal domain and numerous Laminin EGF-like (LE) and Fibronectin type III (FN3) repeats. Mutations of USH2A are scattered throughout the gene and mostly private. Annotating these variants is therefore of major importance to correctly assign pathogenicity. We have extensively genotyped a novel cohort of 152 Usher patients and identified 158 different mutations, of which 93 are newly described. Pooling this new data with the existing pathogenic variants already incorporated in USHbases reveals several previously unappreciated features of the mutational spectrum. We show that parts of the protein are more likely to tolerate single amino acid variations, whereas others constitute pathogenic missense hotspots. We have found, in repeated LE and FN3 domains, a nonequal distribution of the missense mutations that highlights some crucial positions in usherin with possible consequences for the assessment of the pathogenicity of the numerous missense variants identified in USH2A.

Original languageEnglish
Pages (from-to)1179-1186
Number of pages8
JournalHuman Mutation
Issue number10
Publication statusPublished - Oct 1 2014


  • Fibronectin type III
  • Laminin EGF like
  • LSDB
  • USH2A
  • Usher syndrome
  • Usherin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)


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