Fabry Disease 2011

Summary

Fabry disease is a rare genetic disease, that is inherited via the X chromosome and causes a defect in the gene GAL. It is a Lysosomal storage disease and therefor causes a wide range of symptoms. The disease is named after the German Johannes Fabry, who described the disease in 1898 simultaneous with William Anderson from UK.

Phenotype

Symptoms

As the effects caused by the enzymatic disfunction summarize over time, the symptoms evolve progressive. The symptoms occuring during childhood, are generally not specific for Fabry disease, thus it is rarely diagnosed at that stage. The most significant symptom for Fabry disease are dark red skin rashes, that usually evolve during adolescence. The most restrictive and dangerous symptoms emerge at an age of ~30-35.<ref name=fabrycom>http://www.fabrycommunity.com/en/Patients/Education/Progression.aspx</ref>

Childhood

• Pain and burning in the hands and feet
• Impaired sweating
• Psychological and social issues
• Low tolerance for exercise
• Eye abnormalities

Adolescence

• Dark red skin rashes (angiokeratomas)
• Fatigue
• Gastrointestinal problems

Adulthood

• Heart problems
• Kidney problems
• Nervous system problems
• Hearing problems

Cross-references

See also description of this disease in

• Wikipedia
• HGMD
• OMIM:Fabry Disease
• PubMed
• NINDS
• GHR
• NCBI Bookshelf
• Medscape

α-galactosidase A

Gene

The location of the gene GLA on the X chromosome.

The protein α-galactosidase A is encoded by the gene GLA, which is locacted on the X chromosome (gene map locus: Xq22). The gene has an overall length of 10,222 nucleotides and consist of 7 exons (1,290 nucleotides) and 6 introns (8,932 nucleotides).

Cross-references

• NCBI: GLA
• OMIM: GLA
• KEGG: GLA
• Genetics Home Reference: GLA

Protein

Representation of the protein α-galactosidase A.

α-galactosidase A is a homodimeric protein that consist of 398 amino acids. It is a glycosidase (EC number: 3.2.1.22) and hydrolyses O- and S-glycosidic bonds of glycolipids.

Cross-references

• KEGG: EC 3.2.1.22
• MetaCyc: α-Galactosidase A
• PDB: 1R47
• UniProt: α-galactosidase A
• Wikipedia: α-galactosidase A

Biochemical disease mechanism

Glycosphingolipid biosynthesis of Homo sapiens. The disease associated enzyme is highlighted in red.

The hydrolysation of globotriaosylceramide (GL3) to lactosylceramide (GL2) and galactose is catalyzed by the protein α-galactosidase A.

Mutations of the gene GLA influence the enzyme α-galactosidase A. These mutations can affect the synthesis, kinetic properties and stability<ref name=bernstein>Bernstein et al. "Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.", J Clin Invest 1989 Apr, PubMed</ref> of the enzyme which leads to an decreased enzyme activity. Hence the catabolization of glycosphingolipids is not done properly which is especially the case for the breakdown of globotriaosylceramide (GL3) to lactosylceramide (GL2) and galactose. The accumulation of the glycosphingolipids leads to the progressively arising symptoms of the Fabry disease. Since the α-galactosidase A is located in the lysosome Fabry disease is categorized as an lysosomal storage disorder.

Cross-references

• KEGG: Fabry Disease
• KEGG: Glycosphingolipid biosynthesis

Mutations

Currently there are 494 mutations known of the GLA gene in HGMD (as of 2011/05/15)<ref name=HGMD>http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GLA</ref>. 492 of these mutations are associated with Fabry disease, for one mutation there is a uncertainty about the association and one mutation leads to an increased transcription of GLA. A great majority (about 70%) of the associated mutations are missense/nonsense mutations.

Reference sequence

• Nucleotide sequence
• Amino acid sequence

References

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