title: Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.
abstract: 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.
authors.affiliation: CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, F-34000, France.
authors.forename: David
authors.initials: D
authors.lastname: Baux
authors.forename: Catherine
authors.initials: C
authors.lastname: Blanchet
authors.forename: Christian
authors.initials: C
authors.lastname: Hamel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.forename: Lise
authors.initials: L
authors.lastname: Larrieu
authors.forename: Valérie
authors.initials: V
authors.lastname: Faugère
authors.forename: Christel
authors.initials: C
authors.lastname: Vaché
authors.forename: Pierangela
authors.initials: P
authors.lastname: Castorina
authors.forename: Bernard
authors.initials: B
authors.lastname: Puech
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Sue
authors.initials: S
authors.lastname: Malcolm
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Roux
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D060005:Genotyping Techniques; D006801:Humans; D009154:Mutation; D052245:Usher Syndromes / Q000235:genetics* / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C112735:USH2A protein, human
keywords: Fibronectin type III; LSDB; Laminin EGF like; USH2A; Usherin; usher syndrome