Gaucher Disease 2011

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. 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 types.
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. Type3 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 corneal opacities.
Patients of all types show an enlarged spleen and liver and often have liver malfunction. They also have skeletal disorders, bone lesions and sometimes osteoporosis. Patients also have a swelling of the lymph nodes, low blood platelets and anemia. They have a brownish skin and yellow fatty deposits on the white of the eye. In type 3 and mainly in type 2 they show severe neurologic disorders.
Look at the image to see the different symptomes and their severity respective to the type of Gaucher Disease.

Source: http://www.glogster.com/media/1/3/76/87/3768778.gif

Cross-references

See also description of this disease in

• Wikipedia
• NINDS
• MedlinePlus
• MedicalBiochemistryPage
• HGMD
• OMIM
• PubMed

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 these 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.

Sphingolipid metabolism - Homo sapiens (human) (source: KEGG) highlighting disease associated enzymes

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.

Function

Acid-β-Glucosidase (also called Glucocerebrosidase) is responsible for breaking down glucosylceramide into ceramide and glucose in lysosomes.

Structure

Acid-β-glucosidase is a peripheral membrane protein which consists of three domains. The catalytic site is located in Domain III, a (β/α)8 TIM barrel.

Cross-references

• PDB 1OGS (Human acid-beta-glucosidase)
• NCBI (GBA glucosidase, beta, acid)
• Ensembl (Gene: GBA)

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.
Current knowledge about mutations associated with the disease. - Separate into disease causing and neutral mutations.

Reference sequence

Which sequence does not cause the disease and is most often found in the population.

• Create a page for the reference sequence. -- These sequence pages will be the starting point for collecting prediction results and result discussions.

Neutral mutations

• Create one page per mutated sequence.

Disease causing mutations

• Create one page per mutated sequence.