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Plasma mutant α -galactosidase A protein and globotriaosylsphingosine level in Fabry disease

View Article: PubMed Central - PubMed

ABSTRACT

Fabry disease is an X-linked genetic disorder characterized by deficient activity of α-galactosidase A (GLA) and accumulation of glycolipids, and various GLA gene mutations lead to a wide range of clinical phenotypes from the classic form to the later-onset one. To investigate the biochemical heterogeneity and elucidate the basis of the disease using available clinical samples, we measured GLA activity, GLA protein and accumulated globotriaosylsphingosine (Lyso-Gb3), a biomarker of this disease, in plasma samples from Fabry patients. The analysis revealed that both the enzyme activity and the protein level were apparently decreased, and the enzyme activity was well correlated with the protein level in many Fabry patients. In these cases, a defect of biosynthesis or excessive degradation of mutant GLAs should be involved in the pathogenesis, and the residual protein level would determine the accumulation of Lyso-Gb3 and the severity of the disease. However, there are some exceptional cases, i.e., ones harboring p.C142Y, p.R112H and p.M296I, who exhibit a considerable amount of GLA protein. Especially, a subset of Fabry patients with p.R112H or p.M296I has been attracted interest because the patients exhibit almost normal plasma Lyso-Gb3 concentration. Structural analysis revealed that C142Y causes a structural change at the entrance of the active site. It will lead to a complete enzyme activity deficiency, resulting in a high level of plasma Lyso-Gb3 and the classic Fabry disease. On the other hand, it is thought that R112H causes a relatively large structural change on the molecular surface, and M296I a small one in a restricted region from the core to the surface, both the structural changes being far from the active site. These changes will cause not only partial degradation but also degeneration of the mutant GLA proteins, and the degenerated enzymes exhibiting small and residual activity remain and probably facilitate degradation of Lyso-Gb3 in plasma, leading to the later-onset phenotype. The results of this comprehensive analysis will be useful for elucidation of the basis of Fabry disease.

No MeSH data available.


GLA protein concentrations in plasma samples. Classic Fabry males (◆), Later-onset Fabry males (■), Heterozygous Fabry females (▲), Controls (●), Fabry male harboring p.C142Y (◊), Fabry males harboring p.R112H (), and Fabry males harboring p.M296I (□). Box plots show the distribution of cases in each group.
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f0005: GLA protein concentrations in plasma samples. Classic Fabry males (◆), Later-onset Fabry males (■), Heterozygous Fabry females (▲), Controls (●), Fabry male harboring p.C142Y (◊), Fabry males harboring p.R112H (), and Fabry males harboring p.M296I (□). Box plots show the distribution of cases in each group.

Mentions: The plasma GLA protein concentration in the individual case is shown in Table 1, and Fig. 1 summarizes the results of the GLA protein assay. The average plasma GLA levels in the classic Fabry males, later-onset Fabry males, heterozygous Fabry females, and normal subjects were 0.05 ± 0.11 ng/mL (n = 8), 0.93 ± 1.12 ng/mL (n = 12), 1.80 ± 0.96 ng/mL (n = 18), and 3.46 ± 1.04 ng/mL (n = 30), respectively. Most of the Fabry males exhibited lower values than those in the control subjects, the average value for the classic group being lower than that for the later-onset group (p < 0.05). The Fabry heterozygous females exhibited a wide range of GLA protein concentrations, the average value being about half of the normal control mean.


Plasma mutant α -galactosidase A protein and globotriaosylsphingosine level in Fabry disease
GLA protein concentrations in plasma samples. Classic Fabry males (◆), Later-onset Fabry males (■), Heterozygous Fabry females (▲), Controls (●), Fabry male harboring p.C142Y (◊), Fabry males harboring p.R112H (), and Fabry males harboring p.M296I (□). Box plots show the distribution of cases in each group.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121323&req=5

f0005: GLA protein concentrations in plasma samples. Classic Fabry males (◆), Later-onset Fabry males (■), Heterozygous Fabry females (▲), Controls (●), Fabry male harboring p.C142Y (◊), Fabry males harboring p.R112H (), and Fabry males harboring p.M296I (□). Box plots show the distribution of cases in each group.
Mentions: The plasma GLA protein concentration in the individual case is shown in Table 1, and Fig. 1 summarizes the results of the GLA protein assay. The average plasma GLA levels in the classic Fabry males, later-onset Fabry males, heterozygous Fabry females, and normal subjects were 0.05 ± 0.11 ng/mL (n = 8), 0.93 ± 1.12 ng/mL (n = 12), 1.80 ± 0.96 ng/mL (n = 18), and 3.46 ± 1.04 ng/mL (n = 30), respectively. Most of the Fabry males exhibited lower values than those in the control subjects, the average value for the classic group being lower than that for the later-onset group (p < 0.05). The Fabry heterozygous females exhibited a wide range of GLA protein concentrations, the average value being about half of the normal control mean.

View Article: PubMed Central - PubMed

ABSTRACT

Fabry disease is an X-linked genetic disorder characterized by deficient activity of &alpha;-galactosidase A (GLA) and accumulation of glycolipids, and various GLA gene mutations lead to a wide range of clinical phenotypes from the classic form to the later-onset one. To investigate the biochemical heterogeneity and elucidate the basis of the disease using available clinical samples, we measured GLA activity, GLA protein and accumulated globotriaosylsphingosine (Lyso-Gb3), a biomarker of this disease, in plasma samples from Fabry patients. The analysis revealed that both the enzyme activity and the protein level were apparently decreased, and the enzyme activity was well correlated with the protein level in many Fabry patients. In these cases, a defect of biosynthesis or excessive degradation of mutant GLAs should be involved in the pathogenesis, and the residual protein level would determine the accumulation of Lyso-Gb3 and the severity of the disease. However, there are some exceptional cases, i.e., ones harboring p.C142Y, p.R112H and p.M296I, who exhibit a considerable amount of GLA protein. Especially, a subset of Fabry patients with p.R112H or p.M296I has been attracted interest because the patients exhibit almost normal plasma Lyso-Gb3 concentration. Structural analysis revealed that C142Y causes a structural change at the entrance of the active site. It will lead to a complete enzyme activity deficiency, resulting in a high level of plasma Lyso-Gb3 and the classic Fabry disease. On the other hand, it is thought that R112H causes a relatively large structural change on the molecular surface, and M296I a small one in a restricted region from the core to the surface, both the structural changes being far from the active site. These changes will cause not only partial degradation but also degeneration of the mutant GLA proteins, and the degenerated enzymes exhibiting small and residual activity remain and probably facilitate degradation of Lyso-Gb3 in plasma, leading to the later-onset phenotype. The results of this comprehensive analysis will be useful for elucidation of the basis of Fabry disease.

No MeSH data available.