Gaucher Disease 2012

Biochemical disease mechanisms

Gaucher disease (GD) is the most prevalent lipid storage disease. It is caused by mutations in the enzyme glucosylceramidase (glucocerebrosidase) which catalysis the hydrolysis of glucosylceramide to glucose and ceramide in the lysosome.

Glucosylceramide is a ceramide (sphingolipid) with a glucose residue which occurs in the lipid bilayer of red and white blood cells. Worn out blood cells are digested by macrophages which normally break down glucosylceramide in their lysosomes. In GD patients, however, glucosylceramide accumulates due to the deficiency or lower activity of glucosylceramidase. Consequently, Glucosylceramide is "stored" in the lysosomes impairing the function of macrophages which are referred to as Gaucher cells. These Gaucher cells exhibit lysosomes filled with glucosylceramide lipids on light microscopy and aggregate in various parts in the body, in particular in the spleen and liver where they lead to the typical clinical symptoms associated with the GD. GD is related to Fabry disease which are both lipid storage diseases induced by enzymatic dysfunctionalities in the sphingolipid metabolism pathway.

The Sphingolipid metabolism.

A Gaucher cell whose lysosome is stuffed with glycosylceramid.

Glycosylceramidase

Glucosylceramidase (EC 3.2.1.45) is a hydrolase which breaks down glucosylceramide to glucose and ceramide (see above):

• Alternative names:
  • Beta-glucocerebrosidase
  • acid β-glucosidase
  • D-glucosyl-N-acylsphingosine glucohydrolase
• Enzymatic classification: Hydrolase
• Location: lysosomal lipid bilayer membrane in humans
• Length: 497 bp
• Weight: 55.6 KD
• Domains:
  • Chain A: Glycosyl hydrolase domain; TIM beta/alpha-barrel domain
  • Chain B: Glycosyl hydrolase domain; TIM beta/alpha-barrel domain
• Structures: 1OGS 2NT0 3GXI 2V3F 2V3D 2V3E 2NSX 2VT0 3GXM

Cross-references

PROSITE BRENA EC2PDB

UniProtKB/Swiss-Prot ExplorEnz PRIAM enzyme-specific profiles

KEGG Ligand Database for Enzyme Nomenclature IUBMB Enzyme Nomenclature IntEnz

MEDLINE MetaCyc

GBA

Position of GBA on chromosome 1.

The glucosylceramidase gene is labed GBA (GBA1, GCB, GLUC) and located on the q arm of chromosome 1 at position 21 (1q21). It is about 7.6 kb long and contains 11 exons as well as 10 introns which are known to be spliced in different ways resulting in various transcripts. The tissue level of GBA mRNA vary among different cell lines. High levels were reported in epithelial and fibroblast cell lines. There is a highly homologous pseudogene (GBAP) located 16 kb downstream with a sequence identity of 96%. It has been shown that recombination events between GBA and GBAP can cause mutations involved in GD.

Cross-references

NCBI-GI NCBI-GeneID OMIM

HGNC HPRD Ensembl

Vega UniProt

Mutations

GD is an autosomal recessive disease requiring two mutated alleles for being elicited. Both females and males are affected in the same way. GD is highly polymorphic: about 250 mutations have been reported from which 203 are missense mutations, 18 nonsense mutations, 36 small insertions or deletions, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations. These mutations were associated with the three types of GD. However, there is only a weak genotype-phenotype relationship since the phenotype depends on mutations of both alleles and many other factors including environmental and infectious exposures and various genetic modifiers.