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GLA protein 350 to 359 helical wheel |
OMIM allele associated with Fabry Disease: 300644.0001
Clinical impact of variant: This substitution alters the lysosomal enzyme alpha-galactosidase A’s kinetic properties and stability and alters the glycosphingolipid metabolic pathway. The substitution of Arginine to Tryptophan at position 356 results in deficient activity of the α-GAL enzyme. Partial or complete deficiency of α-GAL results in an inability to catabolize lipids with terminal α-galactosyl residues. These lipids, particularly globotriaosylceramide (GL-3; Gb3, ceramide trihexoside, or CTH), accumulate progressively in lysosomes in multiple cell types throughout the body resulting primarily in progressive multisystemic damage to the kidney, heart, and cerebrovascular system.
Protein Analysis: The substitution from amino acid Arginine(R) to Tryptophan (W) at position 356 of the protein changes the secondary structure as well as the hydropathy of the protein. In the normal protein Arginine (R) is hydrophilic and is in a beta region of the protein. In the R356W variant, Tryptophan (W) is hydrophobic and is in an alpha region of the protein. The R356W substitution, however, causes no changes in the transmembrane regions of the protein.
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GLA protein 356R hydrophilic |
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R356W variant, 356W hydrophobic |
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GLA protein secondary structure, 356R in beta region |
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R356W variant secondary structure, 356W in alpha region |
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