Gaucher Disease

A Closer Look

Ray Molzon

Introduction

Lysosomal storage disease (Sphingolipidose)Deficiency of glucocerebrosidase causes

buildup of glucocerebrosideGaucher cells, store sphingolipid in spleen,

liver, bone marrow, alveolar spaces, brain tissue

Symptoms

AnemiaReduced platelet countBone demineralizationJaundiceHepatosplenomegalyNeurologic effects (ataxia, seizures, …)

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 birthsDeath usually occurs w/in 1 year

Type III (Chronic neuropathic/Norbottnian)1 in 50,000 live births

The Gene

GBALocated on 1q21

11 exons, mRNA 1610bpPotential promoters: 2 TATA & 2 CAT

2 ATG start sites, both equally efficient

GBAPLocated ~16kb downstream of GBA

The Enzyme

Reaction catalyzed:D-glucosyl-N-acylsphingosine + H2O <=>

D-glucose + N-acylsphingosine

536 peptidesSignal peptide: 1-39aaGlu235 (acid/base catalyst) and Glu340

(nucleophile) predicted to be in active region5 potential glycosylation sites

Member of O-glycosyl hydrolase 30 family

Mutations

Over 150 GBA mutations identifiedNot 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

Single bp substitution in exon 10Produces new cleavage site for NCiI

endonucleaseProtein has only 497 aa

Same mutation in GBAPHomozygosity associated w/ Type III

Found to be cause of Norbottnian subtypeRecombinant allele found w/ Type II

N370S

Single bp (A to G) in exon 9Found only in Type I patientsGene frequency of .035 in Ashkenazi

Much rarer in general population

Appears to prevent neuropathic symptoms in patients with L444P allele

84GG

Insertion mutation of G at cDNA 84Also very common in Ashkenazi populationN370S found to have .957 linkage

disequilibrium w/ neighboring PKLR A1 allele84GG has 1.00 linkage disequilibrium w/ A6 allele

of PKLRSupports hypothesis that both mutations originated

in individual founders

IVS2

Single bp substitution in splice donor site of intron 2Causes skipping of exon 2

Accounts for .034 of disease alleles in Ashkenzaki

84GG & IVS2 both result in no enzyme

Treatment

Splenectomy (rarely cures)Gene therapyEnzyme replacement

Placental glucorcerebrosidase (Ceredase)$382,200/year for 70kg patient!

Bone marrow transplantationTreatment of choice in advanced disease

Chemical chaperone treatmentFound to aid folding of N370S mutation

Phylogeny

Tidbits

Identity Matrix

Hs GBA Hs GBAP Pt GBAP Gg GBAP

Hs GBA 1.000 94.953 92.605 92.037Hs GBAP 1.000 92.605 92.037Pt GBAP 1.000 98.537Gg GBAP 1.000

Pseudogene is recent in evolutionary history

ReferencesObtained medical info from various sources:

Obtained genetic/molecular info from:

Used GCG for sequence comparisons