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.

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

“…Approximately 30 different homozygous genotypes have been reported in the literature (Table 2). There is clearly a dosage effect with some alleles, such as c.354G4C (K79N), c.680A4G (N188S) or c.1246G4A (G377S), where homozygosity for the mutation results in type 1 disease, while compound heterozygosity with a null allele leads to a type 3 phenotype [Germain et al, 1998;Kim et al, 1996;Park et al, 2003;Zhao et al, 2003a]. Likewise, individuals homozygous for c.754T4A (F213I) or c.1448T4C (L444P) usually develop chronic neuronopathic GD [Ida et al, 1996;Koprivica et al, 2000], but either mutation together with a null allele is more likely to have a type 2 phenotype [Stone et al, 2000b].…”

High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients

“…These observations suggest the possibility of an allele-dose effect, whereby two copies of G377S would lead to an enzymatic residual activity sufficient to prevent neurological involvement, but one copy of G377S with a second severe mutation would lead to type 3 GD. An allele dose-effect has already been described for mutation K79N (31). In this model, the residual activity of mutant enzymes produced by the two alleles should be considered in an additive manner.…”

“…In this model, the residual activity of mutant enzymes produced by the two alleles should be considered in an additive manner. Some mutations, such as G377S, K79N, N188S, V394L, and R463C could be at the limit of residual activity that elicits neuropathic symptoms (3,16,31).…”

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

“…In type I patients, the degradation of blood cell derived glucosylceramide is blocked, but there is sufficient enzyme activity in the CNS to break down ganglioside-derived glucosylceramide, thus preventing its accumulation in the brain . In types II and III, however, there is less residual lysosomal enzyme activity (Brady, 1966), which is insufficient to degrade ganglioside-derived GCS in the CNS (Brady et al, 1965Zhao et al, 2003).…”