NIH Research Festival
Gaucher disease (GD) is a recessive lysosomal storage disorder caused by mutations in GBA1, the gene coding for the hydrolase glucocerebrosidase (GCase). Type 2, the actute neuronopathic form and most severe form of GD, presents with symptoms either prenatally or during infancy, and patients usually die before the age of 3 years. In order to study the pathogenesis of neuronopathic type 2 GD we have generated a new mouse model by crossing two previously described mouse lines: the knock-in point mutation Leu444Pro (c.1448T>G) and an effectively null gba allele created through the targeted disruption of mouse GCase (ΔMGC). A GCase null /Leu444Pro genotype is common among patients with type 2 GD. The Leu444Pro/ΔMGC mice were non-viable, dying within the first few hours after birth, with GCase protein and enzymatic activity levels in different tissues similar to levels in homozygous null gba mice. However, Leu444Pro/ΔMGC mice do not show the lipid storage observed in the homozygous null gba mice, and thus the cause of death remains unknown. While brain LIMP-2 levels were unaltered in these mice, there is some evidence of enhanced neuroinflammation, shown by increased levels of one GFAP isoform in the brains from the Leu444Pro/ΔMGC mice compared to wild type controls. To identify factors contributing to this lethality, ultrastructural studies of skin are being performed and other indicators of neuroinflammation are being evaluated. These mice may offer a new model in which to study the pathogenesis of neuronopathic GD as well as other possible functions of GCase.
Scientific Focus Area: Genetics and Genomics
This page was last updated on Friday, March 26, 2021