1. A Closer Look Ray Molzon
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 GBAP 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: 536 peptides
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 Pseudogene is recent in evolutionary history 1.000 94.953
Identity Matrix
Hs GBA
Hs GBAP
Pt GBAP
Gg GBAP
1.000
94.953
92.605
92.037
98.537

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