AN IMMUNOGLOBULIN SWITCHLIKE SEQUENCE IS LINKED WITH CANINE NARCOLEPSY

Canine narcolepsy is an animal model of the human disorder that is tra nsmitted as a single autosomal recessive gene with full penetrance (ca narc-1) in Dobermans and Labradors. In previous experiments, we have i dentified a very tight linkage marker for canarc-1. This marker, a 0.8 5-kb band cross reacting with a human mu-switch Heavy-Chain Immunoglob ulin probe (maximum logarithm of odds [LOD] score Zmax = 10.8 at 0% re combination), has now been cloned and sequenced. The gene, composed of GC rich repeats, is 75% homologous to the human mu-switch gene and is similar in organization to immunoglobulin switch genes. Curiously, ho wever, this mu-switchlike segment appears to be unlinked with other sw itchlike polymorphisms detected at high stringency with the human mu-s witch probe. Because in most animal species all switch genes are locat ed within 300-500 kb and show tight linkage in families, this result s uggests two possible hypotheses: 1) Our 0.85 kb is a true immunoglobul in switch segment, but the map of the canine Variable Heavy-Chain loci is organized in unlinked clusters, or 2) our 0.85-kb segment is not a n immunoglobulin switch segment and is located elsewhere in the genome in all species. We are now using chromosome walking and Yeast Artific ial Chromosome Cloning techniques, together with corresponding studies in humans to identify the pathological gene.