FAMILIAL EOSINOPHILIA MAPS TO THE CYTOKINE GENE-CLUSTER ON HUMAN CHROMOSOMAL REGION 5Q31-Q33

Familial eosinophilia (FE) is an autosomal dominant disorder character ized by peripheral hypereosinophilia of unidentifiable cause with or w ithout other organ involvement. To localize the gene for FE, we perfor med a genomewide search in a large U.S. kindred, using 312 different p olymorphic markers. Seventeen affected subjects, 28 unaffected bloodli ne relatives, and 8 spouses were genotyped. The initial linkage result s from the genome scan provided evidence for linkage on chromosome 5q3 1-q33. Additional genotyping of genetic markers located in this specif ic region demonstrated significant evidence that the FE locus is situa ted between the chromosome 5q markers D5S642 and D5S816 (multipoint LO D score of 6.49). Notably, this region contains the cytokine gene clus ter, which includes three genes-namely, those for interleukin (IL)-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF)-wh ose products play important roles in the development and proliferation of eosinophils. These three cytokine genes were screened for potentia l disease-specific mutations by resequencing of a subgroup of individu als from the present kindred. No functional sequence polymorphisms wer e found within the promoter, the exons, or the introns of any of these genes or within the IL-3/CM-CSF enhancer, suggesting that the primary defect in FE is not caused by a mutation in any one of these genes bu t, rather, is caused by another gene in the area.