USHER-SYNDROME IN THE SAMARITANS - STRENGTHS AND LIMITATIONS OF USINGINBRED ISOLATED POPULATIONS TO IDENTIFY GENES CAUSING RECESSIVE DISORDERS

We have previously reported significant linkage between markers on 11q 13.5 and Usher syndrome type 1 (USH1B) in a large Samaritan kindred. U SH1B is an autosomal recessive disease characterized by profound conge nital sensorineural deafness, vestibular dysfunction and progressive v isual loss, A unique haplotype found only in all USH1B carriers and af fected individuals implied that the disease-causing mutation probably entered the community from a single founder. Screening for mutations i n a gene called GARP, which was mapped to the same genetic interval as USH1B, revealed a base substitution in the coding region of the gene, in a homozygous state in all affected individuals. This base substitu tion, which results in an arginine to tryptophane change, is not found in control individuals and occurs at an amino acid residue that is co nserved across species, including mouse, gorilla, chimpanzee and macaq ue. This study emphasizes the strength of using an isolated inbred pop ulation for efficient identification of the primary linkage and for na rrowing the disease interval, but also demonstrates its limitations in distinguishing between mutations causing the disease and those repres enting unique and private polymorphisms. (C) 1997 Wiley-Lies, Inc.