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We characterized microsatellite marker haplotypes and identified mutations in members of 19 ethnically diverse Israeli families affected by Wilson disease (WD). Eighteen unique haplotypes were derived from allelic combinations for four marker loci spanning the WD gene, ATP7B, at chromosome 13q14.3: D13S133, D13S296, D13S301 and D13S295. Most of these haplotypes are population specific and vary among and even within different ethnic groups. Intrafamilial variability of WD haplotypes was observed in two large consanguineous families in which a single origin of WD was expected. In contrast, some WD haplotypes were identified in more than one group. Five novel and four previously described mutations were detected in our sample. The novel mutations include two deletions (845delT and 1639delC) and three missense mutations (E1064A, M645R, and G1213V). Mutations were identified for 11 of the 18 WD haplotypes, suggesting that other mutations may reside in noncoding regions of the ATP7B gene. Identification of all WD mutations will undoubtedly increase our understanding of the normal function of ATP7B as well as lead to more accurate prognosis and genetic counseling.

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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.

We examined a large consanguineous Druze family with McArdle disease for mutations in the glycogen myophosphorylase (PYGM) gene. All affected subjects were autozygous for a single G to A transition that abolishes the 5' consensus splice site in the first nucleotide of intron 14. The G to A transition is a rare mutation, with only one previous report in a single white subject heterozygous for this mutation and another, more common, mutation at codon 49. The kindred in our study is the first family reported in which disease is caused by homozygosity for this rare mutation. This kindred was originally reported as the first familial case of McArdle disease in the Druze.