Gaucher Disease 2011
Contents
Summary
Gaucher Disease is a lysosomal storage disease, which was first described by Philippe Gaucher in 1882. It is a genetic disease, which is caused by a recessive autosomal mutation in the gene GBA. It causes accumulation of glucosylceramide, because the enzyme glucocerebrosidase does not work or not correctly. Therefore the patients show several symptomes which are described below. Respective to the severity and the symptomes of the disease, it is subdivided into three subtypes.
The diagnosis is made by genetic testing or it can be detected by biochemical abnormalities (for example high alkaline phosphatase, angiotensin-converting enzyme, immunoglobulin levels). The treatment is only possible for type 1 and partially type 3 by an enzyme replacement therapy.
Phenotype
Gaucher Disease patients show various symptomes caused by the accumulation of glucosylceramide in the cells. The most common form of Gaucher Disease is Type 1, Type 2 is the rarest form and also the worst. Children who have Gaucher Disease Type 2 die at the age of two years.
Type 1 is the adult or nonneuronopathic form, which appears with an age of 30 years. Type 2 is the infantile or neuronopathic form, which appears very early after birth. Type 3 is the juvenile, neuronopathic form, which is again subdevided into three types. Type 3a shows mostly neurologic complications, Type 3b skeletalal and visceral disorders and Type 3c neurological symptomes limited to horizontal supranuclear gaze palsy, cardiac valve calcification and eye disorders.
Patients of all types show:
- an enlarged spleen and liver
- often liver malfunction
- skeletal disorders
- bone lesions
- sometimes osteoporosis
- swelling of the lymph nodes
- low blood platelets
- anemia
- a brownish skin
- yellow fatty deposits on the white of the eye
- in type 3 and mainly in type 2: severe neurologic disorders
Look at the image to see the different symptomes and their severity respective to the type of Gaucher Disease.
Cross-references
See also description of this disease in
- Wikipedia
- NINDS
- MedlinePlus
- MedicalBiochemistryPage
- HGMD
- OMIM: Glucocerebrosidase
- OMIM: Gaucher disease subtypes
- PubMed
- NCBI Bookshelf
Biochemical disease mechanism
The enzyme Glucocerebrosidase (also known as Acid-β-Glucosidase) is located within lysosomes and needed to break down glucocerebroside. People with Gaucher's disease lack the normal form of this enzyme and therefore are not able to degrade glucocerebroside. Latter remains stored within the lysosomes and prevents the macrophages from functioning normally. The macrophages with undigested glucocerebroside are called Gaucher Cells. The abnormal accumulation and storage of glucocerebroside and related sequences can build up to toxic levels and cause the characteristic features of Gaucher disease.
Cross-references
- KEGG: Sphingolipid metabolism
- KEGG: Gaucher disease
- MetaCyc: Function of Glycosylceramidase
- Uniprot: Glucosylceramidase
Acid-β-Glucosidase
Alternative titles: Glucocerebrosidase, Glucosylcerebrosidase.
Gene
The gene coding for Acid-β-Glucosidase is called GBA. It is located on the long arm of chromosome 1 at position 21 from base pair 155,204,239 to base pair 155,214,653 on the reverse strand. It has 11 exons and a cDNA length of about 2.5 kb. 16 kb downstream exists an pseudogene with length 5 kb which has an identity of 96%.
There are two different ATG codons as translation initiation sites. The second one encodes a functional signal sequence of 19 amino acid residues.
Mutations in this gene are associated with Gaucher Disease and Parkinson Disease. It is conserved in vertebrates like chimpanzee, dog, cow, mouse, zebrafish and also in the fruit fly, the mosquito, C.elegans, and the fungi M.grisea, and N.crassa.
Function
Acid-β-Glucosidase (also called Glucocerebrosidase) is a lysosomal membrane-associated glycoprotein. It is an enzyme, which catalyzes the breakdown of glucosylceramide into ceramide and glucose in lysosomes by the hydrolysis of the beta-glucosidic linkage. The interaction with the lipid phospatidylserine and the protein saposin C stimulate its enzymatic activity.
Structure
Acid-β-glucosidase is a peripheral membrane protein which consists of three domains. Three disulfide bonds are responsible for the stability of the three-dimensional structure.
The nascent polypeptide has a length of 536 amino acids. 39 encode a signal sequence that is later cleaved in the endoplasmatic reticulum. The mature protein is build up of 497-amino acids.
The catalytic site is located in Domain III, a (β/α)8 TIM barrel, where glutamine residues 235 and 340 play key roles.
 |
 Reaction: breaking down glucosylceramide into ceramide and glucose Source: http://de.wikipedia.org/wiki/Glucocerebrosidase |
 PDB-structure of Acid-β-glucosidase Source: http://www.rcsb.org/pdb/images/1ogs_bio_r_500.jpg?bioNum=1 |
Cross-references
- PDB: 1OGS (Human acid-beta-glucosidase)
- NCBI: GBA glucosidase, beta, acid
- Ensembl: GBA-Gene
- NCBI Bookshelf
Mutations
Currently 303 mutations of the GBA-gene are listed in HGMD (as of 2011/05/13) whereof 299 are known to cause Gaucher's disease. Most of these mutations reduce or inhibit the catalytic activity of Glucosylceramidase even though not all af them are located at or near the active site of the protein.
Four of these mutations are responsible for about 90% of the disease-causing alleles in the Ashkenazi Jewish population, and only 50-60% in non-Jewish populations.
Frequency of Genotypes
| Genotype | % of Ashkenazi Jewish Individuals | % of Non-Jewish Individuals |
| N370S/L444P | 41% | 9% |
| N370S/L444P | 3% | 19% |
| N370S/c84-85insG | 23% | 0% |
| N370S/IVS2+1G>A | 6% | 2% |
| N370S/V394L | 8% | 0% |
| N370S/RecNciI | 0% | 4% |
Source: NCBI Bookshelf
| Mutations | % of Affected Individuals |
| N370S/N370S | 29% |
| N370S/? | 20% |
| N370S/L444P | 16% |
| N370S/84GG | 12% |
| L444P/L444P | 6% |
| L444P/? | 3% |
| N370S/IVS2+1 | 3% |
Source: NCBI Bookshelf
Reference sequence
Neutral mutations
Coming soon.
Disease causing mutations
Comming soon.
