Spectrum of mutations in USH2A in British patients with Usher syndrome type II

Usher syndrome (USH) is a combination of a progressive pigmentary retinopat hy, indistinguishable from retinitis pigmentosa, and some degree of sensori neural hearing loss. USH can be subdivided in Usher type I (USHI), type II (USHII) and type III (USHIII), all of which are inherited as autosomal rece ssive traits. The three subtypes are genetically heterogeneous, with six lo ci so far identified for USHI, three for USHII and only one for USHIII. Mut ations in a novel gene, USH2A, encoding the protein usherin, have recently been shown to be associated with USHII. The gene encodes a protein with par tial sequence homology to both laminin epidermal growth factor and fibronec tin motifs. We analysed 35 British and one Pakistani Usher type IL families with at least one affected member, for sequence changes in the 20 translat ed exons of the USH2A gene, using heteroduplex analysis and sequencing. Pro bable disease causing mutations in USH2A were identified in 15 of 36 (41.7 %) Usher II families. The most frequently encountered mutation (11/15 famil ies or 11/18 mutated alleles) was del2299G in exon 13, resulting in a frame shift and premature stop codon. Other mutations include insertions and poin t mutations, of which two are previously unreported. Five different polymor phisms were also detected. Our results indicate that mutations in this gene are responsible for disease in a large proportion of British Usher type II patients. Moreover, if screening for mutations in USH2A is considered, it is sensible to screen for the del2299G mutation first. (C) 2001 Academic Pr ess.