The multiple cases of Fabry disease in a Russian family caused by an E341K amino acid substitution in the α-galactosidase A

Beyer, E.; Карпова, Е.А.; Udalova, O.V; Amstel, Hans Kristian Ploos van; Diggelen, O. P. van; Tsvetkova, Inna V.

doi:10.1016/s0009-8981(98)00133-8

Cited by 4 publications

(1 citation statement)

References 12 publications

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“…Among them, only one novel mutation was located in the active site (p.L206P). Different nucleotide substitutions, in position M42 (M42T, M42V), D165 (D165H, D165V), G183 (G183S, G183R), C223 (C223Y), P293 (P293T) and E341 (E341D, E341K), have been reported by other groups who also reported the classic phenotype [11, 12, 16, 18, 33–35]. These results indicate that these positions are very important to the conformation and function of α-gal A.…”

Section: Discussionmentioning

confidence: 74%

Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease

Pan

Wang

et al. 2016

PLoS ONE

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Numerous α-galactosidase A (α-gal A) gene (GLA) mutations have been identified in Fabry disease (FD), but studies on genotype-phenotype correlation are limited. This study evaluated the features of GLA gene mutations and genotype-phenotype relationship in Chinese FD patients. Gene sequencing results, demographic information, clinical history, and laboratory findings were collected from 73 Chinese FD patients. Totally 47 mutations were identified, including 23 novel mutations which might be pathogenic. For male patients, those with frameshift and nonsense mutations presented the classical FD, whereas those with missense mutations presented both of classical and atypical phenotypes. Interestingly, two male patients with missense mutation p.R356G from two unrelated families, and two with p.R301Q from one family presented different phenotypes. A statistically significant association was found between the levels of α-gal A enzyme activity and ocular changes in males, though no significant association was found between residual enzyme activity level and genotype or clinical phenotypes. For female patients, six out of seven with frameshift mutations and one out of nine with missense mutation presented the classical FD, and α-gal A activity in those patients was found to be significantly lower than that of patients with atypical phenotypes (13.73 vs. 46.32 nmol/ml/h/mg). Our findings suggest that the α-gal A activity might be associated with the clinical severity in female patients with FD. But no obvious associations between activity level of α-gal A and genotype or clinical phenotypes were found for male patients.

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Section: Discussionmentioning

confidence: 74%

Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease

Pan

Wang

et al. 2016

PLoS ONE

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The Structure of Human α-Galactosidase A and Implications for Fabry Disease

Guce

Garman

2010

Fabry Disease

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Characterization of two α-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease

Kase

Bierfreund

Klein

et al. 2000

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The mutant products Q279E ((279)Gln to Glu) and R301Q ((301)Arg to Gln) of the X-chromosomal inherited alpha-galactosidase (EC 3.2.1. 22) gene, found in unrelated male patients with variant Fabry disease (late-onset cardiac form) were characterized. In contrast to patients with classic Fabry disease, who have no detectable alpha-galactosidase activity, atypical variants have residual enzyme activity. First, the properties of insect cell-derived recombinant enzymes were studied. The K(m) and V(max) values of Q279E, R301Q, and wild-type alpha-galactosidase toward an artificial substrate, 4-methylumbelliferyl-alpha-D-galactopyranoside, were almost the same. In order to mimic intralysosomal conditions, the degradation of the natural substrate, globotriaosylceramide, by the alpha-galactosidases was analyzed in a detergent-free-liposomal system, in the presence of sphingolipid activator protein B (SAP-B, saposin B). Kinetic analysis revealed that there was no difference in the degradative activity between the mutants and wild-type alpha-galactosidase activity toward the natural substrate. Then, immunotitration studies were carried out to determine the amounts of the mutant gene products naturally occurring in cells. Cultured lymphoblasts, L-57 (Q279E) and L-148 (R301Q), from patients with variant Fabry disease, and L-20 (wild-type) from a normal subject were used. The 50% precipitation doses were 7% (L-57) and 10% (L-148) of that for normal lymphoblast L-20, respectively. The residual alpha-galactosidase activity was 3 and 5% of the normal level in L-57 and L-148, respectively. The quantities of immuno cross-reacting materials roughly correlated with the residual alpha-galactosidase activities in lymphoblast cells from the patients. Compared to normal control cells, fibroblast cells from a patient with variant Fabry disease, Q279E mutation, secreted only small amounts of alpha-galactosidase activity even in the presence of 10 mM NH(4)Cl. It is concluded that Q279E and R301Q substitutions do not significantly affect the enzymatic activity, but the mutant protein levels are decreased presumably in the ER of the cells.

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The multiple cases of Fabry disease in a Russian family caused by an E341K amino acid substitution in the α-galactosidase A

Cited by 4 publications

References 12 publications

Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease

Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease

The Structure of Human α-Galactosidase A and Implications for Fabry Disease

Characterization of two α-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease

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