Identification of a novelde novo mutation (G373D) in the ?-galactosidase A gene (GLA) in a patient affected with Fabry disease

Germain, Dominique P.; Salard, Dominique; Fellmann, Florence; Azibi, K.; Caillaud, Catherine; Bernard, Marie-Agnès; Poënaru, Livia

doi:10.1002/humu.41

Cited by 10 publications

(8 citation statements)

References 3 publications

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“…Although several papers reported the de novo mutation of Fabry patients [22], [23], [24], [25], the frequency of de novo mutations of FD has been unclear. Rodriguez-Mari et al studied 22 families with Fabry disease and detected a de novo mutation [24] and the frequency of de novo mutation in Spain was 4.5% (1 of 22 families).…”

Section: Discussionmentioning

confidence: 99%

Frequency of de novo mutations in Japanese patients with Fabry disease

Kobayashi

Ohashi

Iizuka

et al. 2014

Molecular Genetics and Metabolism Reports

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We examined alpha-galactosidase A (GLA) gene mutations in 74 Japanese families with Fabry disease (FD) to determine the frequency of de novo mutations. In 5 of 74 families (6.8%), the probands had no positive family histories and were diagnosed as de novo because their parents had no mutations in GLA gene. The parents of Fabry patients do not necessarily have mutations in GLA gene which is an important consideration in genetic counseling for FD.

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Section: Discussionmentioning

confidence: 99%

Frequency of de novo mutations in Japanese patients with Fabry disease

Kobayashi

Ohashi

Iizuka

et al. 2014

Molecular Genetics and Metabolism Reports

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“…were identified in classic Fabry disease patients. Four mutations (A97V, R112H, R301Q and G373D) [7,28,32,[35][36][37] were found in both mild classic and variant patients, and P146S was found in a presymptomatic patients [38]. COS-7 cells were transfected with expression vectors encoding various mutant α-Gal A cDNAs and cultivated in the presence of DGJ (to ensure maximum production of the mutant enzymes).…”

Section: Expression and Purification Of Mutant α-Gal A Enzymes In Cosmentioning

confidence: 99%

Mutant α-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin

Ishii

Chang

Kawasaki

et al. 2007

Biochemical Journal

135

134

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Fabry disease is a lysosomal storage disorder caused by the deficiency of alpha-Gal A (alpha-galactosidase A) activity. In order to understand the molecular mechanism underlying alpha-Gal A deficiency in Fabry disease patients with residual enzyme activity, enzymes with different missense mutations were purified from transfected COS-7 cells and the biochemical properties were characterized. The mutant enzymes detected in variant patients (A20P, E66Q, M72V, I91T, R112H, F113L, N215S, Q279E, M296I, M296V and R301Q), and those found mostly in mild classic patients (A97V, A156V, L166V and R356W) appeared to have normal K(m) and V(max) values. The degradation of all mutants (except E59K) was partially inhibited by treatment with kifunensine, a selective inhibitor of ER (endoplasmic reticulum) alpha-mannosidase I. Metabolic labelling and subcellular fractionation studies in COS-7 cells expressing the L166V and R301Q alpha-Gal A mutants indicated that the mutant protein was retained in the ER and degraded without processing. Addition of DGJ (1-deoxygalactonojirimycin) to the culture medium of COS-7 cells transfected with a large set of missense mutant alpha-Gal A cDNAs effectively increased both enzyme activity and protein yield. DGJ was capable of normalizing intracellular processing of mutant alpha-Gal A found in both classic (L166V) and variant (R301Q) Fabry disease patients. In addition, the residual enzyme activity in fibroblasts or lymphoblasts from both classic and variant hemizygous Fabry disease patients carrying a variety of missense mutations could be substantially increased by cultivation of the cells with DGJ. These results indicate that a large proportion of mutant enzymes in patients with residual enzyme activity are kinetically active. Excessive degradation in the ER could be responsible for the deficiency of enzyme activity in vivo, and the DGJ approach may be broadly applicable to Fabry disease patients with missense mutations.

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“…This was a classically affected family as well (Patients 8-1, 8-2, and 8-3, Table 1); this deletion caused a frameshift from codon 278 to a premature termination codon at position 281. In the remaining 4 families, 4 previously reported missense mutations (R112C, C142Y, M296I, and G373D) were identified (Table 3) [4,14,[24][25][26].…”

Section: Resultsmentioning

confidence: 99%