Difference between revisions of "Gaucher Disease 2011"

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== Summary ==
  
== 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 subtypes. <br/>
 +
Gaucher Disease is the most prevalent Lysosomal Storage Disorder (LSD) and was first described by Philippe Gaucher in 1882. The genetic disease is caused by a recessive autosomal mutation in the gene GBA. The mutation leads to a mal- or disfunction of the enzyme glucocerebrosidase 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. <br/>
−
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 ==
  
== 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.<br/>
 +
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 and its progression.<br/>
−
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.
 +
'''Type 1''', also called the adult or nonneuronopathic form, is the most common form of Gaucher's Disease and is most prevalent in the Ashkenazi Jewish population. In this form the symptoms (described below) may appear anytime from childhood to adulthood. '''Type 2''', the infantile or acute neuronopathic form, appears very early after birth and is lethal within one or two years. In addition to the symptoms listed below, this form of disease can cause abnormal eye movements, seizures and brain damage. '''Type 3''' is the juvenile, chronic neuronopathic form, which also affects the nervous system but progresses more slowly than Type 2. Type 3 is further subdivided into three subtypes: Type 3a shows mostly neurologic complications, Type 3b exhibits skeletal and visceral disorders and Type 3c manifests neurological symptomes limited to horizontal supranuclear gaze palsy, cardiac valve calcification and eye disorders.
−
<br/>
 +
<br/><br/>
  +
[[Image:Gaucher_disease_symptomes_types.jpg|thumb|Symptomes and their severity respective to the type of Gaucher Disease <br/>Source: http://www.glogster.com/media/1/3/76/87/3768778.gif]]
−
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.<br/>
 
  +
'''Possible symptomes:'''<br/>
−
Look at the image to see the different symptomes and their severity respective to the type of Gaucher Disease.
  
  +
* enlarged spleen and liver
−
[[Image:Gaucher_disease_symptomes_types.jpg|thumb|Source: http://www.glogster.com/media/1/3/76/87/3768778.gif]]<br/><br/>
  
  +
* 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<br/>
  +
   
 
=== Cross-references ===
 
=== Cross-references ===
Line 20: Line 31:
 
* [http://themedicalbiochemistrypage.org/gaucherdisease.html MedicalBiochemistryPage]
  
* [http://themedicalbiochemistrypage.org/gaucherdisease.html MedicalBiochemistryPage]
 
* [http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GBA HGMD]
  
* [http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GBA HGMD]
−
* [http://www.ncbi.nlm.nih.gov/omim/606463 OMIM]
 +
* [http://www.ncbi.nlm.nih.gov/omim/606463 OMIM: Glucocerebrosidase]
  +
* [http://www.ncbi.nlm.nih.gov/omim/230800,230900,231000,231005,606463,608013 OMIM: Gaucher disease subtypes]
 
* [http://www.ncbi.nlm.nih.gov/pubmed?term=Gaucher%20Disease PubMed]
  
* [http://www.ncbi.nlm.nih.gov/pubmed?term=Gaucher%20Disease PubMed]
  +
* [http://www.ncbi.nlm.nih.gov/books/NBK1269/ NCBI Bookshelf]
  +
  +
== Diagnosis ==
  +
  +
There are different tests to diagnose Gaucher disease <ref>http://www.mayoclinic.com/health/gauchers-disease/DS00972/DSECTION=tests-and-diagnosis</ref>:
  +
* '''Enzyme analysis''': The level of glucocerebrosidase is measured by using a blood test. People with Gaucher's disease show a low level of the enzyme. The enzyme level of carriers falls between those of affected people and those of non-carriers.
  +
* '''Genetic mutation analysis''': This test looks for genetic mutations which are known to cause Gaucher's disease. The test is not considered definitive as not all genetic mutations involved in the disease are known.
  +
Furthermore it can be detected by biochemical abnormalities (for example high alkaline phosphatase, angiotensin-converting enzyme, immunoglobulin levels).
  +
  +
== Treatment ==
  +
  +
Gaucher disease type 1 can be treated with two different therapies <ref>http://www.gaucher.org.uk/gaucher_disease.php?show=en&id=54</ref>:
  +
* '''Enzyme replacement therapy''' antagonizes the deficient in glucocerebrosidase enzymatic activity by injecting a modified glucocerebrosidase enzyme.
  +
* '''Substrate reduction therapy''' tries to limit the amount of undigested glucosylceramide so that it can be processed despite the reduced activity of glucocerebroside.
  +
  +
Enzyme replacement therapy does not treat the neurologic disorders of type 2 and 3 disease. As the enzyme is not able to cross the blood-brain barrier, the treatment only affects the visceral involvement but the brain involvement is still able to progress. <ref>http://www.gaucherdisease.org/gaucher_2_3.php</ref>
   
 
== Biochemical disease mechanism ==
  
== 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.
 +
The enzyme Glucocerebrosidase which is located within lysosomes is needed to break down glucocerebroside. People with Gaucher's disease do not have the normal form of this enzyme and therefore are not able to degrade glucocerebroside. The 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 leads to the characteristic features of Gaucher disease. <ref>http://www.gaucher.org.uk/gaucher_disease.php?show=en&id=48</ref>
   
 
[[Image:Gaucher_disease_kegg.png|thumb|right|Sphingolipid metabolism - Homo sapiens (human) (source: KEGG) highlighting disease associated enzymes]]
  
[[Image:Gaucher_disease_kegg.png|thumb|right|Sphingolipid metabolism - Homo sapiens (human) (source: KEGG) highlighting disease associated enzymes]]
Line 34: Line 62:
 
* [http://biocyc.org/META/NEW-IMAGE?type=NIL&object=GLUCOSYLCERAMIDASE-RXN&redirect=T MetaCyc: Function of Glycosylceramidase]
  
* [http://biocyc.org/META/NEW-IMAGE?type=NIL&object=GLUCOSYLCERAMIDASE-RXN&redirect=T MetaCyc: Function of Glycosylceramidase]
 
* [http://www.uniprot.org/uniprot/P04062 Uniprot: Glucosylceramidase]
  
* [http://www.uniprot.org/uniprot/P04062 Uniprot: Glucosylceramidase]
−
<br/>
 +
<br clear="all"/>
−
<br/>
  
−
<br/>
  
−
<br/>
  
   
−
== Acid-β-Glucosidase ==
 +
== Glucocerebrosidase ==
−
Alternative titles: Glucocerebrosidase, Glucosylcerebrosidase.
 +
Alternative titles: Acid-β-Glucosidase, Glycosylceramidase.
   
 
=== Gene ===
  
=== 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.
+
The gene coding for Glucocerebrosidase 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%.<br/>
  +
There are two different ATG codons as translation initiation sites. The second one encodes a functional signal sequence of 19 amino acid residues.
  +
<br/>
  +
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 ===
  
=== Function ===
  +
Glucocerebrosidase is a lysosomal membrane-associated glycoprotein. It is an enzyme, which catalyzes the breakdown of Glucocerebroside (also called Glucosylceramide) into ceramide and glucose by hydrolyzing its beta-glucosidic linkage. The interaction with the lipid phosphatidylserine and the protein saposin C stimulates its enzymatic activity.
−
Acid-β-Glucosidase (also called Glucocerebrosidase) is responsible for breaking down glucosylceramide into ceramide and glucose in lysosomes.
 
   
 
=== Structure ===
  
=== 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.
 +
Glucocerebrosidase is a peripheral membrane protein which consists of three domains. Three disulfide bonds are responsible for the stability of the three-dimensional structure. The catalytic site is located in Domain III, a (β/α)8 TIM barrel, where glutamine residues 235 and 340 play key roles.<br/>
  +
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.<br/>
  +
The active site of the enzyme consists of two amino acids: Glu235 and Glu340.
  +
<br clear="all"/>
  +
  +
{| class="centered"
  +
| [[Image:GBA.jpg|thumb|Gene location in chromosome 1<br/>Source: http://ghr.nlm.nih.gov/dynamicImages/chromomap/GBA.jpeg]]
  +
| [[Image:Gba_reaction.jpg|thumb|Reaction: breaking down glucosylceramide into ceramide and glucose<br/>Source: http://de.wikipedia.org/wiki/Glucocerebrosidase]]
  +
| [[Image:Glucocerebrosidase.jpg|thumb|PDB-structure of Glucocerebrosidase<br/> Source: http://www.rcsb.org/pdb/images/1ogs_bio_r_500.jpg?bioNum=1]]
  +
|}
   
 
=== Cross-references ===
  
=== Cross-references ===
Line 55: Line 93:
 
* [http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=full_report&list_uids=2629 NCBI: GBA glucosidase, beta, acid]
  
* [http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=full_report&list_uids=2629 NCBI: GBA glucosidase, beta, acid]
 
* [http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177628;r=1:155204239-155214653 Ensembl: GBA-Gene]
  
* [http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177628;r=1:155204239-155214653 Ensembl: GBA-Gene]
  +
* [http://www.ncbi.nlm.nih.gov/books/NBK1269/ NCBI Bookshelf]
   
 
== Mutations ==
  
== 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.
+
Currently 303 mutations of the GBA-gene are listed in HGMD <ref>http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GBA</ref> (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 Glucocerebrosidase 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>
 
<br/>
  
<br/>
  +
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 ===
   
  +
{| border="1" style="text-align:center; border-spacing:0;"
  +
|'''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: [http://www.ncbi.nlm.nih.gov/books/NBK1269/ NCBI Bookshelf]
  +
  +
{| border="1" style="text-align:center; border-spacing:0;"
  +
|'''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: [http://www.ncbi.nlm.nih.gov/books/NBK1269/ NCBI Bookshelf]
  +
  +
<br/>
 
=== Reference sequence ===
  
=== Reference sequence ===
   
−
* [[glucocerebrosidase_reference_mrna|mRNA sequence]]
 +
* [[glucocerebrosidase_reference_nucleotide|Nucleotide sequence]]
−
* [[glucocerebrosidase_reference_amino_acid|amino acid sequence]]
 +
* [[glucocerebrosidase_reference_amino_acid|Amino acid sequence]]
   
 
=== Neutral mutations ===
  
=== Neutral mutations ===
  +
−
Comming soon.
  
  +
* [[glucocerebrosidase_neutral_mutations|Amino acid sequence with neutral mutations]]
   
 
=== Disease causing mutations ===
  
=== Disease causing mutations ===
  +
−
Comming soon.
  
  +
* [[glucocerebrosidase_disease_causing_mutations|Amino acid sequence with disease causing mutations]]
  +
  +
== Tasks ==
  +
* [[Glucocerebrosidase_sequence_alignments|Task 2 - Sequence Alignments]]
  +
* [[Glucocerebrosidase_sequence_based_prediction|Task 3 - Sequence-based predictions]]
  +
* [[Glucocerebrosidase_homology_modelling | Task 4 - Homology Modelling ]]
  +
* [[Glucocerebrosidase_mapping_snps | Task 5 - Mapping SNPs ]]
  +
* [[Sequence_based_mutation analysis of GBA|Task 6 - Sequence-based mutation analysis]]
  +
* [[Structure_based_mutation analysis of GBA|Task 7 - Structure-based mutation analysis]]
  +
* [[Sequence_and_structure_based_mutation_analysis of GBA| Task 6 & Task 7 - Sequence- and Structure-based mutation analysis combined]]
  +
* [[Glucocerebrosidase_Molecular_Dynamics_Simulation|Task 8 - Molecular Dynamics Simulation]]
  +
* [[Normal_Mode_Analysis_of_Glucocerebrosidase|Task 9 - Normal Mode Analysis]]
  +
* [[Molecular_Dynamics_Simulations_Analysis_of_Glucocerebrosidase|Task 10 - Molecular Dynamics Simulations Analysis]]
  +
  +
== References ==
  +
  +
<references />
  +
  +
[[Category: Disease 2011]] [[Category:Gaucher_Disease 2011]]

Latest revision as of 13:56, 29 March 2012

Summary

Gaucher Disease is the most prevalent Lysosomal Storage Disorder (LSD) and was first described by Philippe Gaucher in 1882. The genetic disease is caused by a recessive autosomal mutation in the gene GBA. The mutation leads to a mal- or disfunction of the enzyme glucocerebrosidase 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.

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 and its progression.
Type 1, also called the adult or nonneuronopathic form, is the most common form of Gaucher's Disease and is most prevalent in the Ashkenazi Jewish population. In this form the symptoms (described below) may appear anytime from childhood to adulthood. Type 2, the infantile or acute neuronopathic form, appears very early after birth and is lethal within one or two years. In addition to the symptoms listed below, this form of disease can cause abnormal eye movements, seizures and brain damage. Type 3 is the juvenile, chronic neuronopathic form, which also affects the nervous system but progresses more slowly than Type 2. Type 3 is further subdivided into three subtypes: Type 3a shows mostly neurologic complications, Type 3b exhibits skeletal and visceral disorders and Type 3c manifests neurological symptomes limited to horizontal supranuclear gaze palsy, cardiac valve calcification and eye disorders.

Symptomes and their severity respective to the type of Gaucher Disease
Source: http://www.glogster.com/media/1/3/76/87/3768778.gif

Possible symptomes:

  • 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


Cross-references

See also description of this disease in

Diagnosis

There are different tests to diagnose Gaucher disease <ref>http://www.mayoclinic.com/health/gauchers-disease/DS00972/DSECTION=tests-and-diagnosis</ref>:

  • Enzyme analysis: The level of glucocerebrosidase is measured by using a blood test. People with Gaucher's disease show a low level of the enzyme. The enzyme level of carriers falls between those of affected people and those of non-carriers.
  • Genetic mutation analysis: This test looks for genetic mutations which are known to cause Gaucher's disease. The test is not considered definitive as not all genetic mutations involved in the disease are known.

Furthermore it can be detected by biochemical abnormalities (for example high alkaline phosphatase, angiotensin-converting enzyme, immunoglobulin levels).

Treatment

Gaucher disease type 1 can be treated with two different therapies <ref>http://www.gaucher.org.uk/gaucher_disease.php?show=en&id=54</ref>:

  • Enzyme replacement therapy antagonizes the deficient in glucocerebrosidase enzymatic activity by injecting a modified glucocerebrosidase enzyme.
  • Substrate reduction therapy tries to limit the amount of undigested glucosylceramide so that it can be processed despite the reduced activity of glucocerebroside.

Enzyme replacement therapy does not treat the neurologic disorders of type 2 and 3 disease. As the enzyme is not able to cross the blood-brain barrier, the treatment only affects the visceral involvement but the brain involvement is still able to progress. <ref>http://www.gaucherdisease.org/gaucher_2_3.php</ref>

Biochemical disease mechanism

The enzyme Glucocerebrosidase which is located within lysosomes is needed to break down glucocerebroside. People with Gaucher's disease do not have the normal form of this enzyme and therefore are not able to degrade glucocerebroside. The 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 leads to the characteristic features of Gaucher disease. <ref>http://www.gaucher.org.uk/gaucher_disease.php?show=en&id=48</ref>

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

Cross-references


Glucocerebrosidase

Alternative titles: Acid-β-Glucosidase, Glycosylceramidase.

Gene

The gene coding for Glucocerebrosidase 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

Glucocerebrosidase is a lysosomal membrane-associated glycoprotein. It is an enzyme, which catalyzes the breakdown of Glucocerebroside (also called Glucosylceramide) into ceramide and glucose by hydrolyzing its beta-glucosidic linkage. The interaction with the lipid phosphatidylserine and the protein saposin C stimulates its enzymatic activity.

Structure

Glucocerebrosidase is a peripheral membrane protein which consists of three domains. Three disulfide bonds are responsible for the stability of the three-dimensional structure. The catalytic site is located in Domain III, a (β/α)8 TIM barrel, where glutamine residues 235 and 340 play key roles.
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 active site of the enzyme consists of two amino acids: Glu235 and Glu340.

Gene location in chromosome 1
Source: http://ghr.nlm.nih.gov/dynamicImages/chromomap/GBA.jpeg
Reaction: breaking down glucosylceramide into ceramide and glucose
Source: http://de.wikipedia.org/wiki/Glucocerebrosidase
PDB-structure of Glucocerebrosidase
Source: http://www.rcsb.org/pdb/images/1ogs_bio_r_500.jpg?bioNum=1

Cross-references

Mutations

Currently 303 mutations of the GBA-gene are listed in HGMD <ref>http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GBA</ref> (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 Glucocerebrosidase 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

Disease causing mutations

Tasks

References

<references />

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