Screening for pharmacological chaperones in Fabry disease

Shin, Sanghoon; Murray, Gary J.; Kluepfel-Stahl, Stefanie; Cooney, Adele; Quirk, Jane M.; Schiffmann, Raphael; Brady, Roscoe O.; Kaneski, Christine R.

doi:10.1016/j.bbrc.2007.05.082

Cited by 47 publications

(44 citation statements)

References 20 publications

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“…These small molecules can not only be delivered orally to reach all tissue types, but also they have the ability to increase the residual enzyme activity. 22,23 We contributed to the Fabry mutation database in identifying a new point mutation c.124A4G (p.M42V) in the fibroblasts of one Fabry patient analyzed.…”

Section: Discussionmentioning

confidence: 99%

Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

et al. 2008

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Total or partial deficiency of the human lysosomal hydrolase a-galactosidase A is responsible for Fabry disease, the X-linked inborn error of glycosphingolipid metabolism. Together with the predominant a-galactosidase A gene mRNA product encoding the lysosomal enzyme, a weakly regulated alternatively spliced a-galactosidase A transcript is expressed in normal tissues, but its overexpression, due to the intronic g.9331G4A mutation, leads to the cardiac variant. We report the molecular characterization of five Fabry patients including two siblings. Sequencing analysis of the a-galactosidase A gene coding region and intron/exon boundaries identified the new c.124A4G (p.M42V) genetic lesion as well as a known deletion in three patients, whereas in the two remaining patients, no mutations were identified. To evaluate possible a-galactosidase A gene transcription alterations, both predominant and alternatively spliced mRNAs were quantified by absolute real-time PCR on total RNA preparations from the patients' fibroblasts. An impressive reduction in the predominant a-galactosidase A transcript was detected in the last patients (Pt 4 and Pt 5). However, the alternatively spliced mRNA was dramatically overexpressed in one of them, carrying a new intronic lesion (g.9273C4T). These findings strongly suggest a correlation between this new intronic mutation and the unbalanced a-galactosidase A mRNAs ratio, which could therefore be responsible for the reduced enzyme activity causing Fabry disease. The real-time assay developed here to investigate the two a-galactosidase A mRNAs might play a crucial role in revealing possible genetic lesions and in confirming the pathogenetic mechanisms underlying Fabry disease.

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Section: Discussionmentioning

confidence: 99%

Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

et al. 2008

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“…Galactose and its structural analog DGJ are well known chemical chaperones that bind the active site of GLA and act as competitive inhibitors (Garman and Garboczi, 2004;Fan et al, 2007). Binding promotes proper folding, dimerization, and processing of the GLA protein, thereby enhancing residual GLA activity in patients with GLA deficiencies (Frustaci et al, 2001;Matsuzawa et al, 2005;Ishii et al, 2007;Shin et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Effects of a chemical chaperone on genetic mutations in α-galactosidase A in Korean patients with Fabry disease

Park

Kim

et al. 2009

Exp Mol Med

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Fabry disease is an X-linked inborn error of glycosphingolipid catabolism that results from mutations in the gene encoding the α-galactosidase A (GLA) enzyme. We have identified 15 distinct mutations in the GLA gene in 13 unrelated patients with classic Fabry disease and 2 unrelated patients with atypical Fabry disease. Two of the identified mutations were novel (i.e., the D231G missense mutation and the L268delfsX1 deletion mutation). This study evaluated the effects of the chemical chaperones 1-deoxygalactonojirimycin (DGJ) on the function of GLA in vitro, in cells containing missense mutations in the GLA gene. Nine missense and a nonsense mutations, including one novel mutation were cloned into mammalian expression vectors. After transient expression in COS-7 cells, GLA enzyme activity and protein expression were analyzed using fluorescence spectrophotometry and Western blot analysis, respectively. DGJ enhanced GLA enzyme activity in the M42V, I91T, R112C and F113L mutants. Interestingly, the I91T and F113L mutations are associated with the atypical form of Fabry disease. However, DGJ treatment did not have any significant effect on the GLA enzyme activity and protein expression of other mutants, including C142W, D231G, D266N, and S297F. Of note, GLA enzyme activity was not detected in the novel mutant (i.e., D231G), although protein expression was similar to the wild type. In the absence of DGJ, the E66Q mutant had wild-type levels of GLA protein expression and approximately 40% GLA activity, indicating that E66Q is either a mild mutation or a functional single nucleotide polymorphism (SNP). Thus, the results of this study suggest that the chemical chaperone DGJ enhances GLA enzyme activity and protein expression in milder mutations associated with the atypical form of Fabry disease.

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“…Like other chemical chaperones they are small molecules capable of traversing the cell membrane and encouraging protein folding through non-covalent interactions [21]. Pharmacological chaperones can be protein ligands that bind the nascent protein or recover a late-folded mutant protein [28]. However, since they interact, presumably, only with their target protein they generally effective at a lower concentration.…”

Section: Chemical Chaperone Applicationsmentioning

confidence: 99%

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

Sauer

Patel

Chan

et al. 2008

Expert Review of Ophthalmology

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SUMMARYRecent studies suggest that pathological processes involved in age-related macular degeneration (AMD) might induce endoplasmic reticulum (ER) stress. Growing evidence demonstrates the ability of chemical chaperones to decrease ER stress and ameliorate ER stress-related disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for AMD. In this review, we examine the evidence suggesting a role for ER stress in AMD. Furthermore, we discuss the use of chaperone therapy for the treatment of ER stress-associated diseases, including other neurodegenerative diseases and retinopathies. Finally, we examine strategies for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human disease.

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Screening for pharmacological chaperones in Fabry disease

Cited by 47 publications

References 20 publications

Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

Effects of a chemical chaperone on genetic mutations in α-galactosidase A in Korean patients with Fabry disease

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

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