Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 Gaucher disease

Gaucher disease is an autosomal recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal hydrolase, ac id beta-glucosidase. Three phenotypically distinct subtypes result from dif ferent acid beta-glucosidase mutations encoding enzymes with absent or low activity. A severe neonatal type 2 variant who presented with collodion ski n, ichthyosis, and a rapid neurodegenerative course had two novel acid beta -glucosidase alleles: a complex, maternally derived allele, E326K+L444P, an d a paternally inherited nonsense mutation, E233X. Because the only other n on-pseudogene-derived complex allele, D140H+E326K, also had the E326K lesio n and was reported in a mild type 1 patient with a D140H+E326K/K157Q genoty pe, these complex alleles and their individual mutations were expressed and characterized. Because the E233X mutation expressed no activity and the K1 57Q allele had similar to 1% normal specific activity based on cross-reacti ng immunologic material (CRIM SA) in the baculovirus system, the residual a ctivity in both patients was primarily from their complex alleles. In the t ype 1 patient, the D140H+E326K allele was neuroprotective, encoding an enzy me with a catalytic efficiency similar to that of the N370S enzyme. In cont rast, the E326K+L444P allele did not have sufficient activity to protect ag ainst the neurologic manifestations and, in combination with the inactive E 233X lesion, resulted in the severe neonatal type 2 variant. Thus, characte rization of these novel genotypes with non-pseudogene-derived complex mutat ions provided the pathogenic basis for their diverse phenotypes.