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Gaucher Disease. A Closer Look Ray Molzon. 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. Symptoms. Anemia

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gaucher disease

Gaucher Disease

A Closer Look

Ray Molzon

introduction
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
symptoms
Symptoms
  • Anemia
  • Reduced platelet count
  • Bone demineralization
  • Jaundice
  • Hepatosplenomegaly
  • Neurologic effects (ataxia, seizures, …)
diagnosis
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
the gene
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
the enzyme
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
mutations
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
l444p
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
n370s
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
slide10
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
slide11
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
treatment
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
tidbits
Tidbits
  • Pseudogene is recent in evolutionary history
references
References
  • Obtained medical info from various sources:
  • Obtained genetic/molecular info from:
  • Used GCG for sequence comparisons