title: Gaucher disease: in vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes.
abstract: 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.
authors.affiliation: Division and Program in Human Genetics, Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: Huiquan
authors.initials: H
authors.lastname: Zhao
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Bailey
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Elsas
authors.forename: Karen A
authors.initials: KA
authors.lastname: Grinzaid
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: D004247:DNA; D005962:Glucosylceramidase