Gaucher disease is a lysosomal storage disease caused by deficiency of the enzyme glucocerebrosidase, leading to a buildup of glucocerebroside in cells. There are three main types of Gaucher disease: type I is the most common non-neurological form, type II is fatal in infants, and type III involves neurological symptoms. The disease is caused by mutations in the GBA gene encoding glucocerebrosidase. Over 150 mutations have been identified, with four accounting for 95% of cases in Ashkenazi Jews. Treatment options include enzyme replacement therapy, bone marrow transplantation, and chemical chaperones.

1. Gaucher Disease
A Closer Look
Ray Molzon

2. Introduction
Lysosomal storage disease
(Sphingolipidose)
Deficiency of glucocerebrosidase causes
buildup of glucocerebroside
Gaucher cells, store sphingolipid in spleen,
liver, bone marrow, alveolar spaces, brain
tissue

3. Symptoms
Anemia
Reduced platelet count
Bone demineralization
Jaundice
Hepatosplenomegaly
Neurologic effects (ataxia, seizures, …)

4. Diagnosis
Three recognized types:
Type I (Noncerebral juvenile)
Most common in Ashkenazi Jew lineage (1:450)
Type II (Infantile cerebral)
1 in 100,000 live births
Death usually occurs w/in 1 year
Type III (Chronic neuropathic/Norbottnian)
1 in 50,000 live births

5. The Gene
GBA
Located on 1q21
11 exons, mRNA 1610bp
Potential promoters: 2 TATA & 2 CAT
2 ATG start sites, both equally efficient
GBAP
Located ~16kb downstream of GBA

6. The Enzyme
Reaction catalyzed:
D-glucosyl-N-acylsphingosine + H2O <=>
D-glucose + N-acylsphingosine
536 peptides
Signal peptide: 1-39aa
Glu235 (acid/base catalyst) and Glu340
(nucleophile) predicted to be in active region
5 potential glycosylation sites
Member of O-glycosyl hydrolase 30 family

7. Mutations
Over 150 GBA mutations identified
Not all proven to cause disease
4 account for disease in 95% of
Ashkenazi Jewish population, 50% of
general pop.
Many found to be identical to mutations
in pseudogene

8. L444P
Single bp substitution in exon 10
Produces new cleavage site for NCiI
endonuclease
Protein has only 497 aa
Same mutation in GBAP
Homozygosity associated w/ Type III
Found to be cause of Norbottnian subtype
Recombinant allele found w/ Type II

9. N370S
Single bp (A to G) in exon 9
Found only in Type I patients
Gene frequency of .035 in Ashkenazi
Much rarer in general population
Appears to prevent neuropathic
symptoms in patients with L444P allele

10. 84GG
Insertion mutation of G at cDNA 84
Also very common in Ashkenazi population
N370S found to have .957 linkage
disequilibrium w/ neighboring PKLR A1 allele
84GG has 1.00 linkage disequilibrium w/ A6 allele
of PKLR
Supports hypothesis that both mutations originated
in individual founders

11. IVS2
Single bp substitution in splice donor site
of intron 2
Causes skipping of exon 2
Accounts for .034 of disease alleles in
Ashkenzaki
84GG & IVS2 both result in no enzyme

12. Treatment
Splenectomy (rarely cures)
Gene therapy
Enzyme replacement
Placental glucorcerebrosidase (Ceredase)
$382,200/year for 70kg patient!
Bone marrow transplantation
Treatment of choice in advanced disease
Chemical chaperone treatment
Found to aid folding of N370S mutation

13. Phylogeny

14. Tidbits
Identity
Matrix
Hs GBA Hs GBAP Pt GBAP Gg GBAP
Hs GBA 1.000 94.953 92.605 92.037
Hs GBAP 1.000 92.605 92.037
Pt GBAP 1.000 98.537
Gg GBAP 1.000
Pseudogene is recent in evolutionary history

15. References
Obtained medical info from various sources:
Obtained genetic/molecular info from:
Used GCG for sequence comparisons