| Structural highlights
Disease
[AGAL_HUMAN] Defects in GLA are the cause of Fabry disease (FD) [MIM:301500]. FD is a rare X-linked sphingolipidosis disease where glycolipid accumulates in many tissues. The disease consists of an inborn error of glycosphingolipid catabolism. FD patients show systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes throughout the body. Clinical recognition in males results from characteristic skin lesions (angiokeratomas) over the lower trunk. Patients may show ocular deposits, febrile episodes, and burning pain in the extremities. Death results from renal failure, cardiac or cerebral complications of hypertension or other vascular disease. Heterozygous females may exhibit the disorder in an attenuated form, they are more likely to show corneal opacities.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40]
Publication Abstract from PubMed
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense alpha-galactosidase A (alpha-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin-arylthioureas (DGJ-ArTs), capable of stabilizing alpha-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N'H thiourea proton and the catalytic aspartic acid acid D231 of alpha-Gal A, as confirmed by a 2.55 A resolution cocrystal structure. Selected candidates enhanced alpha-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD.
Molecular Basis of 1-Deoxygalactonojirimycin Arylthiourea Binding to Human alpha-Galactosidase A: Pharmacological Chaperoning Efficacy on Fabry Disease Mutants.,Yu Y, Mena-Barragan T, Higaki K, Johnson JL, Drury JE, Lieberman RL, Nakasone N, Ninomiya H, Tsukimura T, Sakuraba H, Suzuki Y, Nanba E, Mellet CO, Garcia Fernandez JM, Ohno K ACS Chem Biol. 2014 May 12. PMID:24783948[41]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Bernstein HS, Bishop DF, Astrin KH, Kornreich R, Eng CM, Sakuraba H, Desnick RJ. Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J Clin Invest. 1989 Apr;83(4):1390-9. PMID:2539398 doi:https://dx.doi.org/10.1172/JCI114027
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- ↑ Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet. 1993 Dec;53(6):1186-97. PMID:7504405
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- ↑ Davies JP, Eng CM, Hill JA, Malcolm S, MacDermot K, Winchester B, Desnick RJ. Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries. Eur J Hum Genet. 1996;4(4):219-24. PMID:8875188
- ↑ Cariolou MA, Christodoulides M, Manoli P, Kokkofitou A, Tsambaos D. Novel trinucleotide deletion in Fabry's disease. Hum Genet. 1996 Apr;97(4):468-70. PMID:8834244
- ↑ Germain D, Biasotto M, Tosi M, Meo T, Kahn A, Poenaru L. Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. Hum Genet. 1996 Dec;98(6):719-26. PMID:8931708
- ↑ Blanch LC, Meaney C, Morris CP. A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene. Hum Mutat. 1996;8(1):38-43. PMID:8807334 doi:<38::AID-HUMU5>3.0.CO;2-L 10.1002/(SICI)1098-1004(1996)8:1<38::AID-HUMU5>3.0.CO;2-L
- ↑ Redonnet-Vernhet I, Ploos van Amstel JK, Jansen RP, Wevers RA, Salvayre R, Levade T. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene. J Med Genet. 1996 Aug;33(8):682-8. PMID:8863162
- ↑ Takata T, Okumiya T, Hayashibe H, Shimmoto M, Kase R, Itoh K, Utsumi K, Kamei S, Sakuraba H. Screening and detection of gene mutations in Japanese patients with Fabry disease by non-radioactive single-stranded conformation polymorphism analysis. Brain Dev. 1997 Mar;19(2):111-6. PMID:9105656
- ↑ Eng CM, Ashley GA, Burgert TS, Enriquez AL, D'Souza M, Desnick RJ. Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. Mol Med. 1997 Mar;3(3):174-82. PMID:9100224
- ↑ Chen CH, Shyu PW, Wu SJ, Sheu SS, Desnick RJ, Hsiao KJ. Identification of a novel point mutation (S65T) in alpha-galactosidase A gene in Chinese patients with Fabry disease. Mutations in brief no. 169. Online. Hum Mutat. 1998;11(4):328-30. PMID:9554750 doi:<328::AID-HUMU11>3.0.CO;2-N 10.1002/(SICI)1098-1004(1998)11:4<328::AID-HUMU11>3.0.CO;2-N
- ↑ Miyazaki T, Kajita M, Ohmori S, Mizutani N, Niwa T, Murata Y, Seo H. A novel mutation (E358K) in the alpha-galactosidase A gene detected in a Japanese family with Fabry disease. Hum Mutat. 1998;Suppl 1:S139-40. PMID:9452068
- ↑ Okumiya T, Kawamura O, Itoh K, Kase R, Ishii S, Kamei S, Sakuraba H. Novel missense mutation (M72V) of alpha-galactosidase gene and its expression product in an atypical Fabry hemizygote. Hum Mutat. 1998;Suppl 1:S213-6. PMID:9452090
- ↑ Guffon N, Froissart R, Chevalier-Porst F, Maire I. Mutation analysis in 11 French patients with Fabry disease. Hum Mutat. 1998;Suppl 1:S288-90. PMID:9452111
- ↑ Germain DP, Poenaru L. Fabry disease: identification of novel alpha-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches. Biochem Biophys Res Commun. 1999 Apr 21;257(3):708-13. PMID:10208848 doi:10.1006/bbrc.1999.0310
- ↑ Beyer EM, Karpova EA, Udalova OV, Ploos van Amstel JK, van Diggelen OP, Tsvetkova IV. The multiple cases of Fabry disease in a Russian family caused by an E341K amino acid substitution in the alpha-galactosidase A. Clin Chim Acta. 1999 Feb;280(1-2):81-9. PMID:10090526
- ↑ Kase R, Bierfreund U, Klein A, Kolter T, Utsumi K, Itoha K, Sandhoff K, Sakuraba H. Characterization of two alpha-galactosidase mutants (Q279E and R301Q) found in an atypical variant of Fabry disease. Biochim Biophys Acta. 2000 Jun 15;1501(2-3):227-35. PMID:10838196
- ↑ Topaloglu AK, Ashley GA, Tong B, Shabbeer J, Astrin KH, Eng CM, Desnick RJ. Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease. Mol Med. 1999 Dec;5(12):806-11. PMID:10666480
- ↑ Lee JK, Kim GH, Kim JS, Kim KK, Lee MC, Yoo HW. Identification of four novel mutations in five unrelated Korean families with Fabry disease. Clin Genet. 2000 Sep;58(3):228-33. PMID:11076046
- ↑ Ashton-Prolla P, Tong B, Shabbeer J, Astrin KH, Eng CM, Desnick RJ. Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. J Investig Med. 2000 Jul;48(4):227-35. PMID:10916280
- ↑ Germain DP, Salard D, Fellmann F, Azibi K, Caillaud C, Bernard MC, Poenaru L. Identification of a novel de novo mutation (G373D) in the alpha-galactosidase A gene (GLA) in a patient affected with Fabry disease. Hum Mutat. 2001 Apr;17(4):353. PMID:11295840 doi:10.1002/humu.41
- ↑ Blaydon D, Hill J, Winchester B. Fabry disease: 20 novel GLA mutations in 35 families. Hum Mutat. 2001 Nov;18(5):459. PMID:11668641 doi:10.1002/humu.1219
- ↑ Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, Goldfarb L, Brady RO, Balow JE, Austin Iii HA, Kopp JB. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore). 2002 Mar;81(2):122-38. PMID:11889412
- ↑ Yang CC, Lai LW, Whitehair O, Hwu WL, Chiang SC, Lien YH. Two novel mutations in the alpha-galactosidase A gene in Chinese patients with Fabry disease. Clin Genet. 2003 Mar;63(3):205-9. PMID:12694230
- ↑ Lai LW, Whitehair O, Wu MJ, O'Meara M, Lien YH. Analysis of splice-site mutations of the alpha-galactosidase A gene in Fabry disease. Clin Genet. 2003 Jun;63(6):476-82. PMID:12786754
- ↑ Verovnik F, Benko D, Vujkovac B, Linthorst GE. Remarkable variability in renal disease in a large Slovenian family with Fabry disease. Eur J Hum Genet. 2004 Aug;12(8):678-81. PMID:15162124 doi:10.1038/sj.ejhg.5201184
- ↑ Shabbeer J, Robinson M, Desnick RJ. Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography. Hum Mutat. 2005 Mar;25(3):299-305. PMID:15712228 doi:10.1002/humu.20144
- ↑ Nance CS, Klein CJ, Banikazemi M, Dikman SH, Phelps RG, McArthur JC, Rodriguez M, Desnick RJ. Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch Neurol. 2006 Mar;63(3):453-7. PMID:16533976 doi:63/3/453
- ↑ Hwu WL, Chien YH, Lee NC, Chiang SC, Dobrovolny R, Huang AC, Yeh HY, Chao MC, Lin SJ, Kitagawa T, Desnick RJ, Hsu LW. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat. 2009 Oct;30(10):1397-405. doi: 10.1002/humu.21074. PMID:19621417 doi:10.1002/humu.21074
- ↑ Yu Y, Mena-Barragan T, Higaki K, Johnson JL, Drury JE, Lieberman RL, Nakasone N, Ninomiya H, Tsukimura T, Sakuraba H, Suzuki Y, Nanba E, Mellet CO, Garcia Fernandez JM, Ohno K. Molecular Basis of 1-Deoxygalactonojirimycin Arylthiourea Binding to Human alpha-Galactosidase A: Pharmacological Chaperoning Efficacy on Fabry Disease Mutants. ACS Chem Biol. 2014 May 12. PMID:24783948 doi:https://dx.doi.org/10.1021/cb500143h
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