Usher syndrome in the Samaritans: strengths and limitations of using inbred isolated populations to identify genes causing recessive disorders.
We have previously reported significant linkage between markers on 11q13.5 and Usher syndrome type 1 (USH1B) in a large Samaritan kindred. USH1B is an autosomal recessive disease characterized by profound congenital sensorineural deafness, vestibular dysfunction and progressive visual loss. A unique haplotype found only in all USH1B carriers and affected individuals implied that the disease-causing mutation probably entered the community from a single founder. Screening for mutations in 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 substitution, which results in an arginine to tryptophane change, is not found in control individuals and occurs at an amino acid residue that is conserved across species, including mouse, gorilla, chimpanzee and macaque. This study emphasizes the strength of using an isolated inbred population for efficient identification of the primary linkage and for narrowing the disease interval, but also demonstrates its limitations in distinguishing between mutations causing the disease and those representing unique and private polymorphisms.
Bonné-Tamir
B
B
Department of Human Genetics, Sackler Faculty of Medicine, Tel-Aviv University, Israel. bonne@post.tau.ac.il
Nystuen
A
A
Seroussi
E
E
Kalinsky
H
H
Kwitek-Black
A E
AE
Korostishevsky
M
M
Adato
A
A
Sheffield
V C
VC
D001120:Arginine / Q000737:chemistry; D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11; D003241:Consanguinity; D004247:DNA / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D005828:Genetics, Population; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008877:Middle East / Q000453:epidemiology; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D013577:Syndrome; D014364:Tryptophan / Q000737:chemistry; D015837:Vestibular Diseases / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*; D014786:Vision Disorders / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*
D014364:Tryptophan; D004247:DNA; D001120:Arginine