Gaucher Disease 2012

Summary

Gaucher Disease (GD) is a genetic disease and is known as the most common prevalent Lysosomal Storage disease (LSD). The french doctor Phillipe Gaucher described it originally in 1882 and this disease is named after him. GD is caused by the recessive mutation in gene GBA located in chromosome 1 which leads to the deficiency of the enzyme glucosylceramidase (glucocerebrosidase). This enzyme is needed to catalyze the breakdown of the fatty substance glucosylceramide - a normal part of the cell membrane. The lack of the enzyme therefore leads to the accumulation of glucosylceramide in the cells and organs, mostly in the liver, spleen, bone marrow and nervous system and prevent them from working properly.

recessive genetic diseases frequency among individuals of Ashkenazi Jewish population

GD is found as the most common genetic disease affecting Ashkenazi Jewish people who are originally from Eastern, Central and Northern Europe. Compared with that in the general population(approximately 1 in 50,000 to 1 in 100,000 individuals[1]), the frequency of GD in Ashkenazi Jewish population is quite higher (carrier rate approximately 1 in 15 while the birth incidence is 1 in 900[2]).

Phenotype

ongoing!

The symptoms of GD.

Generally speaking, Gaucher disease can cause symptoms like:

• Anemia
• Fatigue
• Easy Bruising and Bleeding
• Nosebleeds
• Osteoporosis
• Bone pain and easily broken bones
• Swollen stomach due to enlarged liver and/or spleen

There are three clinical subtypes of Gaucher disease:

Type 1 (non-neuropathic GD)
Type 2 (acute infantile neuropathic GD)
Type 3 (chronic neuropathic GD)

Biochemical disease mechanisms

The Sphingolipid metabolism.

A Gaucher cell whose lysosome is stuffed with glycosylceramid.

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 bi-layer 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 that are filled with glucosylceramide lipids and aggregate in various parts in the body where they are causing the disease symptomes metioned above. For instance, Gaucher cells that accumulate in the liver or spline can cause metabolic disorders, whereas accumulations in the brain often lead to cognitive disabilities (Type 2, Type 3). GD is related to Fabry disease which are both lipid storage diseases induced by enzymatic dysfunctionalities in the sphingolipid metabolism pathway.

Glycosylceramidase

Cystal structure of glysosylceramidase (1OGS).

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
• Crystal 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.

GBA in the Ensemble gene browser.

The glucosylceramidase gene is named GBA (GBA1, GCB, GLUC) and is 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 gene 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

Number of mutations per exon associated with Gaucher disease.

GD is an autosomal recessive disease which requires 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 as well as different genetic modifiers. Hence, estimating the phenotype and the severity of disease symptoms is in most cases not feasible even though the gene sequence is known.[3]

Diagnosis

ongoing!

• Enzyme analysis
• Genetic mutation analysis

Treatments

ongoing!

• Enzyme replacement therapy
• Bone marrow transplantation
• Substrate reduction therapy
• Gene therapy

Further reading

• http://en.wikipedia.org/wiki/Gaucher%27s_disease
• http://www.ncbi.nlm.nih.gov/books/NBK1269
• http://www.gaucher.org.uk