Abstract 824 Mechanisms in Hereditary Disease Platform, Tuesday, 5/4

Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase (GC), presents with many clinical phenotypes. Studies of genotype-phenotype correlation indicate that patients who share the same PCR defined point mutation can have a spectrum of manifestations. The human GC gene region on 1q21 is complex, with a duplication which gave rise to pseudogenes for both GC and a convergently transcribed gene, metaxin. Recombination between these two genes and their pseudogenes introduces several recombinant mutant alleles and fusion genes that are encountered in patients with Gaucher disease. We studied 344 alleles from patients with Gaucher disease and identified 32 recombinant alleles, which were more prevalent among patients with the neuronopathic forms of Gaucher disease (12 had type 1, 13 had type 2, and 7 had type 3 Gaucher disease). Recombination occurring on both alleles appears to result in early lethality. Several methods were used to determine the possible mechanism(s) and sites of recombinations, including long-template PCR. Southern blots, and direct sequencing. Among the 32 recombinant alleles, 7 different sites of recombination were identified, occurring within different exons, introns, and the region 3′ to the GC gene. In 85% of these alleles, the site of recombination occurred within introns 8-11. In 6 alleles a deletion of the intergenic region resulted in a fusion gene and 2 alleles appear to have resulted from recombination between the gene for metaxin and its pseudogene. These alleles appear to arise by different mechanisms of recombination, including gene conversion, reciprocal crossover, intramolecular crossover, and Chi structures. Further studies of these recombinations may provide clues to the etiology of the more atypical Gaucher phenotypes.