Velayati A, DePaolo J, Gupta N et al.
National Institutes of Health, Bethesda, MD, USA.
Hum Mutat 2011;32:1232–8.
Editor’s note: The results of this interesting study demonstrate the detrimental effect of combined mutations in the glucocerebrosidase (GBA) gene and the scavenger receptor B2 (SCARB2) gene, which encodes the lysosomal receptor of GBA. These two mutations resulted in a severe neuronopathic phenotype with progressive myoclonic epilepsy and dementia, presenting at the age of 13 years, in one of two siblings with Gaucher disease. Further analysis showed several alterations in the GBA gene in the affected sibling, comprising the same haplotype as in the unaffected sibling. Further analysis of the SCARB2 gene identified a maternally inherited heterozygous mutation in the affected sibling only. Mutations in the SCARB2 gene were recently reported in patients with myoclonic epilepsy with or without nephrotic syndrome. In the affected sibling only, GBA activity, western blot, real-time polymerase chain reaction, and immunofluorescence assays demonstrated markedly reduced levels of the GBA lysosomal receptor protein encoded by the SCARB2 gene. The cells secreted highly glycosylated enzyme and had mistrafficking of GBA. Other SCARB2 mutations were not detected in an analysis of 13 other subjects with myoclonic epilepsy and Gaucher disease and 40 control subjects.