Gaucher disease: in vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes.

Gaucher disease, a common lysosomal storage disorder, is associated with mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals are described to share a common mutant allele, but manifest different clinical categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele). The shared alleles were identical as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (types 1 and 3) in these two patients provide support for a threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.