Gaucher Disease 2011
Contents
Summary
Gaucher Disease is the most prevalent Lysosomal Storage Disorder (LSD) and 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. The mutation leads to a mal- or disfunction of the enzyme glucocerebroside causing an accumulation of glucocerebroside in cells and certain organs.
The course of the disease is very variable and results in many different symptomes. Respective to the severity and the symptomes of the disease, it is subdivided into three clinical 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).
Gaucher disease can be treated with two different therapies: Enzyme replacement therapy and substrate reduction therapy. Former antagonizes the deficient in glucocerebrosidase enzymatic activity by injecting a modified glucocerebrosidase enzyme. The latter tries to reduce the amount of undigested glucosylceramide so that it can be processed despite the reduced activity of glucocerebroside.
In type 2 and 3 it is impossible to treat the neurologic disorders, because you can't inject anything to the brain. Because of the blood-brain barrier the injections don't reach the brain.
Phenotype
Gaucher Disease patients show various symptomes caused by the accumulation of glucosylceramide in the cells. The disease is subdivided into three clinical subtypes, depending on the absence (Type 1) or presence (Type 2 and 3) of primary central nervous system involvement.
Type 1 is the adult or nonneuronopathic form, which appears with an age of 30 years. It is the most common form of Gaucher's Disease. Type 2 is the infantile or neuronopathic form, which appears very early after birth. This type is the rarest form but also the worst. Children who have Gaucher Disease Type 2 die within one or two years 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.
Symptoms common to all three subtypes:
- enlarged spleen and liver
- liver malfunction
- skeletal disorders
- bone lesions
- osteoporosis
- swelling of the lymph nodes
- low blood platelets
- anemia
- brownish skin
- yellow fatty deposits on the white of the eye
- in type 3 and mainly in type 2: severe neurologic disorders
The figure on the right shows the different symptomes and their severity respective to the type of Gaucher Disease.
Diagnosis
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).
Treatment
Gaucher disease can be treated with two different therapies: Enzyme replacement therapy and substrate reduction therapy. Former antagonizes the deficient in glucocerebrosidase enzymatic activity by injecting a modified glucocerebrosidase enzyme. The latter tries to reduce the amount of undigested glucosylceramide so that it can be processed despite the reduced activity of glucocerebroside.
In type 2 and 3 it is impossible to treat the neurologic disorders, because you can't inject anything to the brain. Because of the blood-brain barrier the injections don't reach the brain.
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 stimulates 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. <ref> Dvir H, Harel M, McCarthy AA, et al. X-ray structure of human acid β-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep. 2003;2003:704–709 </ref>
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
Coming soon.
References
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