Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease

Gaucher disease, the most common lysosomal storage disorder, results from t he inherited deficiency of the enzyme glucocerebrosidase, Three clinical ty pes are recognized: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic, Type 2 Gaucher disease, the rarest typ e, is progressive and fatal. We have performed molecular analyses of a coho rt of 31 patients with type 2 Gaucher disease. The cases studied included f etuses presenting prenatally with hydrops fetalis, infants with the collodi on baby phenotype, and infants diagnosed after several months of life. All 62 mutant glucocerebrosidase (GBA) alleles were identified. Thirty three di fferent mutant alleles were found, including point mutations, splice juncti on mutations, deletions, fusion alleles and recombinant alleles. Eleven nov el mutations were identified in these patients: R131L, H255Q, R285H, S196P, H311R, c.330delA, V398F, F259L, c.533delC, Y304C and A190E, Mutation L444P was found on 25 patient alleles. Southern blots and direct sequencing demo nstrated that mutation L444P occurred alone on 9 alleles, with E326K on one allele and as part of a recombinant allele on 15 alleles. There were no ho mozygotes for point mutation L444P, The recombinant alleles that included L 444P resulted from either reciprocal recombination or gene conversion with the nearby glucocerebrosidase pseudogene, and seven different sites of reco mbination were identified. Homozygosity fur a recombinant allele was associ ated with early lethality. We have also summarized the literature describin g mutations associated with type 2 disease, and list 50 different mutations . This report constitutes the most comprehensive molecular study to date of type 2 Gaucher disease, and it demonstrates that there is significant phen otypic and genotypic heterogeneity among patients with type 2 Gaucher disea se. Hum Mutat 15:181-188, 2000, Published 2000 Wiley-Liss, Inc.dagger