Identification of novel USH2A mutations: implications for the structure ofUSH2A protein

Usher syndrome type II is an autosomal recessive disorder, characterised by stable hearing impairment from childhood and progressive retinitis pigment osa from the late teens. Mutations In the USH2A gene, located on 1q41, were recently shown to be responsible for Usher syndrome type IIa. We have inve stigated the molecular pathology of Usher type II by screening the USH2A ge ne for mutations in 31 unrelated patients from Denmark and Norway Besides t he frequent 2299delG mutation, which accounted for 44% of the disease allel es, a heterogeneous spectrum of mutations was identified. Sixteen new, puta tive disease-causing mutations were detected, of which 12 were private and four were shared by unrelated patients. The disease-causing mutations were scattered throughout the gene and included six nonsense and seven missense mutations, two deletions and one small insertion. In addition, six non-path ogenic polymorphisms were identified. All missense mutations resulted in ma jor amino acid side-chain alterations. Four missense mutations affected the N-terminal part of USH2A, whereas three missense mutations affected the la minin-type epidermal growth factor-like (LE) domain. The structural consequ ences of the mutations affecting the LE domain are discussed in relation to the three-dimensional structure of a LE-module of the mouse laminin gamma 1 chain.