| Structural highlights
Disease
GLCM_HUMAN Defects in GBA are the cause of Gaucher disease (GD) [MIM:230800; also known as glucocerebrosidase deficiency. GD is the most prevalent lysosomal storage disease, characterized by accumulation of glucosylceramide in the reticulo-endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset.[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] [41] [42] [43] [44] [45] [46] [47] Defects in GBA are the cause of Gaucher disease type 1 (GD1) [MIM:230800; also known as adult non-neuronopathic Gaucher disease. GD1 is characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved.[:][48] [49] [50] [51] [52] [53] [54] [55] [56] [57] Defects in GBA are the cause of Gaucher disease type 2 (GD2) [MIM:230900; also known as acute neuronopathic Gaucher disease. GD2 is the most severe form and is universally progressive and fatal. It manifests soon after birth, with death generally occurring before patients reach two years of age.[58] [59] [60] [61] [62] [63] [64] [65] Defects in GBA are the cause of Gaucher disease type 3 (GD3) [MIM:231000; also known as subacute neuronopathic Gaucher disease. GD3 has central nervous manifestations.[66] [67] [68] [69] [70] [71] [72] Defects in GBA are the cause of Gaucher disease type 3C (GD3C) [MIM:231005; also known as pseudo-Gaucher disease or Gaucher-like disease.[73] [74] [75] [76] [77] [78] Defects in GBA are the cause of Gaucher disease perinatal lethal (GDPL) [MIM:608013. It is a distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism.[79] [80] [81] [82] [83] [84] Note=Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.[85] [86] [87] [88] [89] [90] Defects in GBA contribute to susceptibility to Parkinson disease (PARK) [MIM:168600. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.[91] [92] [93] [94] [95] [96]
Function
GLCM_HUMAN
Publication Abstract from PubMed
Pharmacologic chaperoning is a therapeutic strategy being developed to improve the cellular folding and trafficking defects associated with Gaucher disease, a lysosomal storage disorder caused by point mutations in the gene encoding acid-beta-glucosidase (GCase). In this approach, small molecules bind to and stabilize mutant folded or nearly folded GCase in the endoplasmic reticulum (ER), increasing the concentration of folded, functional GCase trafficked to the lysosome where the mutant enzyme can hydrolyze the accumulated substrate. To date, the pharmacologic chaperone (PC) candidates that have been investigated largely have been active site-directed inhibitors of GCase, usually containing five- or six-membered rings, such as modified azasugars. Here we show that a seven-membered, nitrogen-containing heterocycle (3,4,5,6-tetrahydroxyazepane) scaffold is also promising for generating PCs for GCase. Crystal structures reveal that the core azepane stabilizes GCase in a variation of its proposed active conformation, whereas binding of an analogue with an N-linked hydroxyethyl tail stabilizes GCase in a conformation in which the active site is covered, also utilizing a loop conformation not seen previously. Although both compounds preferentially stabilize GCase to thermal denaturation at pH 7.4, reflective of the pH in the ER, only the core azepane, which is a mid-micromolar competitive inhibitor, elicits a modest increase in enzyme activity for the neuronopathic G202R and the non-neuronopathic N370S mutant GCase in an intact cell assay. Our results emphasize the importance of the conformational variability of the GCase active site in the design of competitive inhibitors as PCs for Gaucher disease.
Binding of 3,4,5,6-tetrahydroxyazepanes to the acid-beta-glucosidase active site: implications for pharmacological chaperone design for Gaucher disease.,Orwig SD, Tan YL, Grimster NP, Yu Z, Powers ET, Kelly JW, Lieberman RL Biochemistry. 2011 Dec 13;50(49):10647-57. Epub 2011 Nov 14. PMID:22047104[97]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Liou B, Kazimierczuk A, Zhang M, Scott CR, Hegde RS, Grabowski GA. Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. J Biol Chem. 2006 Feb 17;281(7):4242-53. Epub 2005 Nov 17. PMID:16293621 doi:10.1074/jbc.M511110200
- ↑ Beutler E, Gelbart T. Gaucher disease associated with a unique KpnI restriction site: identification of the amino-acid substitution. Ann Hum Genet. 1990 May;54(Pt 2):149-53. PMID:1974409
- ↑ Hong CM, Ohashi T, Yu XJ, Weiler S, Barranger JA. Sequence of two alleles responsible for Gaucher disease. DNA Cell Biol. 1990 May;9(4):233-41. PMID:1972019
- ↑ Beutler E, Gelbart T, West C. Identification of six new Gaucher disease mutations. Genomics. 1993 Jan;15(1):203-5. PMID:8432537 doi:http://dx.doi.org/10.1006/geno.1993.1035
- ↑ Choy FY, Wei C, Applegarth DA, McGillivray BC. DNA analysis of an uncommon missense mutation in a Gaucher disease patient of Jewish-Polish-Russian descent. Am J Med Genet. 1994 Jun 1;51(2):156-60. PMID:7916532 doi:http://dx.doi.org/10.1002/ajmg.1320510216
- ↑ Beutler E, Gelbart T. Two new Gaucher disease mutations. Hum Genet. 1994 Feb;93(2):209-10. PMID:8112750
- ↑ Tuteja R, Tuteja N, Lilliu F, Bembi B, Galanello R, Cao A, Baralle FE. Y418C: a novel mutation in exon 9 of the glucocerebrosidase gene of a patient with Gaucher disease creates a new Bgl I site. Hum Genet. 1994 Sep;94(3):314-5. PMID:8076951
- ↑ Beutler E, Demina A, Gelbart T. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994 Nov;1(1):82-92. PMID:8790604
- ↑ Cormand B, Vilageliu L, Burguera JM, Balcells S, Gonzalez-Duarte R, Grinberg D, Chabas A. Gaucher disease in Spanish patients: analysis of eight mutations. Hum Mutat. 1995;5(4):303-9. PMID:7627184 doi:http://dx.doi.org/10.1002/humu.1380050406
- ↑ Choy FY, Wei C. Identification of a new mutation (P178S) in an African-American patient with type 2 Gaucher disease. Hum Mutat. 1995;5(4):345-7. PMID:7627192 doi:http://dx.doi.org/10.1002/humu.1380050414
- ↑ Morar B, Lane AB. The molecular characterization of Gaucher disease in South Africa. Clin Genet. 1996 Aug;50(2):78-84. PMID:8937765
- ↑ Kim JW, Liou BB, Lai MY, Ponce E, Grabowski GA. Gaucher disease: identification of three new mutations in the Korean and Chinese (Taiwanese) populations. Hum Mutat. 1996;7(3):214-8. PMID:8829654 doi:<214::AID-HUMU5>3.0.CO;2-A 10.1002/(SICI)1098-1004(1996)7:3<214::AID-HUMU5>3.0.CO;2-A
- ↑ Cormand B, Vilageliu L, Balcells S, Gonzalez-Duarte R, Chabas A, Grinberg D. Two novel (1098insA and Y313H) and one rare (R359Q) mutations detected in exon 8 of the beta-glucocerebrosidase gene in Gaucher's disease patients. Hum Mutat. 1996;7(3):272-4. PMID:8829663 doi:<272::AID-HUMU14>3.0.CO;2-# 10.1002/(SICI)1098-1004(1996)7:3<272::AID-HUMU14>3.0.CO;2-#
- ↑ Amaral O, Pinto E, Fortuna M, Lacerda L, Sa Miranda MC. Type 1 Gaucher disease: identification of N396T and prevalence of glucocerebrosidase mutations in the Portuguese. Hum Mutat. 1996;8(3):280-1. PMID:8889591 doi:<280::AID-HUMU15>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1996)8:3<280::AID-HUMU15>3.0.CO;2-Z
- ↑ Seeman PJ, Finckh U, Hoppner J, Lakner V, Liebisch I, Grau G, Rolfs A. Two new missense mutations in a non-Jewish Caucasian family with type 3 Gaucher disease. Neurology. 1996 Apr;46(4):1102-7. PMID:8780099
- ↑ Cormand B, Grinberg D, Gort L, Fiumara A, Barone R, Vilageliu L, Chabas A. Two new mild homozygous mutations in Gaucher disease patients: clinical signs and biochemical analyses. Am J Med Genet. 1997 Jun 27;70(4):437-43. PMID:9182788
- ↑ Choy FY, Humphries ML, Shi H. Identification of two novel and four uncommon missense mutations among chinese Gaucher disease patients. Am J Med Genet. 1997 Aug 8;71(2):172-8. PMID:9217217
- ↑ Hatton CE, Cooper A, Whitehouse C, Wraith JE. Mutation analysis in 46 British and Irish patients with Gaucher's disease. Arch Dis Child. 1997 Jul;77(1):17-22. PMID:9279145
- ↑ Grace ME, Desnick RJ, Pastores GM. Identification and expression of acid beta-glucosidase mutations causing severe type 1 and neurologic type 2 Gaucher disease in non-Jewish patients. J Clin Invest. 1997 May 15;99(10):2530-7. PMID:9153297 doi:10.1172/JCI119437
- ↑ Ida H, Rennert OM, Kawame H, Maekawa K, Eto Y. Mutation prevalence among 47 unrelated Japanese patients with Gaucher disease: identification of four novel mutations. J Inherit Metab Dis. 1997 Mar;20(1):67-73. PMID:9061570
- ↑ Demina A, Beutler E. Six new Gaucher disease mutations. Acta Haematol. 1998;99(2):80-2. PMID:9554454
- ↑ Germain DP, Puech JP, Caillaud C, Kahn A, Poenaru L. Exhaustive screening of the acid beta-glucosidase gene, by fluorescence-assisted mismatch analysis using universal primers: mutation profile and genotype/phenotype correlations in Gaucher disease. Am J Hum Genet. 1998 Aug;63(2):415-27. PMID:9683600 doi:10.1086/301969
- ↑ Choy FY, Humphries ML, Ben-Yoseph Y. Gaucher type 2 disease: identification of a novel transversion mutation in a French-Irish patient. Am J Med Genet. 1998 Jun 16;78(1):92-3. PMID:9637431
- ↑ Beutler E, Gelbart T. Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis. 1998 Mar;24(1):2-8. PMID:9516376 doi:10.1006/bcmd.1998.0165
- ↑ Sinclair G, Choy FY, Humphries L. A novel complex allele and two new point mutations in type 2 (acute neuronopathic) Gaucher disease. Blood Cells Mol Dis. 1998 Dec;24(4):420-7. PMID:9851895 doi:S1079-9796(98)90210-8
- ↑ Parenti G, Filocamo M, Titomanlio L, Rizzolo G, Silvestro E, Perretti A, Gatti R, Andria G. A novel mutation of the beta-glucocerebrosidase gene associated with neurologic manifestations in three sibs. Clin Genet. 1998 Apr;53(4):281-5. PMID:9650766
- ↑ Cormand B, Grinberg D, Gort L, Chabas A, Vilageliu L. Molecular analysis and clinical findings in the Spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome. Hum Mutat. 1998;11(4):295-305. PMID:9554746 doi:<295::AID-HUMU7>3.0.CO;2-6 10.1002/(SICI)1098-1004(1998)11:4<295::AID-HUMU7>3.0.CO;2-6
- ↑ Choy FY, Humphries ML, Ben-Yoseph Y. A novel mutation (V191G) in a German-British type 1 Gaucher disease patient. Mutations in brief no. 131. Online. Hum Mutat. 1998;11(5):411-2. PMID:10206680 doi:<411::AID-HUMU11>3.0.CO;2-2 10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU11>3.0.CO;2-2
- ↑ Wasserstein MP, Martignetti JA, Zeitlin R, Lumerman H, Solomon M, Grace ME, Desnick RJ. Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: identification and expression of a novel acid beta-glucosidase mutation. Am J Med Genet. 1999 Jun 4;84(4):334-9. PMID:10340647
- ↑ Choy FY, Wong K, Shi HP. Glucocerebrosidase mutations among Chinese neuronopathic and non-neuronopathic Gaucher disease patients. Am J Med Genet. 1999 Jun 11;84(5):484-6. PMID:10360404
- ↑ Hodanova K, Hrebicek M, Cervenkova M, Mrazova L, Veprekova L, Zemen J. Analysis of the beta-glucocerebrosidase gene in Czech and Slovak Gaucher patients: mutation profile and description of six novel mutant alleles. Blood Cells Mol Dis. 1999 Oct-Dec;25(5-6):287-98. PMID:10744424
- ↑ Stone DL, van Diggelen OP, de Klerk JB, Gaillard JL, Niermeijer MF, Willemsen R, Tayebi N, Sidransky E. Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease? Eur J Hum Genet. 1999 May-Jun;7(4):505-9. PMID:10352942 doi:10.1038/sj.ejhg.5200315
- ↑ Sarria AJ, Giraldo P, Perez-Calvo JI, Pocovi M. Detection of three rare (G377S, T134P and 1451delAC), and two novel mutations (G195W and Rec[1263del55;1342G>C]] in Spanish Gaucher disease patients. Mutation in brief no. 251. Online. Hum Mutat. 1999;14(1):88. PMID:10447266 doi:<88::AID-HUMU15>3.0.CO;2-H 10.1002/(SICI)1098-1004(1999)14:1<88::AID-HUMU15>3.0.CO;2-H
- ↑ Koprivica V, Stone DL, Park JK, Callahan M, Frisch A, Cohen IJ, Tayebi N, Sidransky E. Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. Am J Hum Genet. 2000 Jun;66(6):1777-86. Epub 2000 May 4. PMID:10796875 doi:10.1086/302925
- ↑ Bodamer OA, Church HJ, Cooper A, Wraith JE, Scott CR, Scaglia F. Variant Gaucher disease characterized by dysmorphic features, absence of cardiovascular involvement, laryngospasm, and compound heterozygosity for a novel mutation (D409H/C16S). Am J Med Genet. 2002 May 15;109(4):328-31. PMID:11992489 doi:10.1002/ajmg.10385
- ↑ Orvisky E, Park JK, Parker A, Walker JM, Martin BM, Stubblefield BK, Uyama E, Tayebi N, Sidransky E. The identification of eight novel glucocerebrosidase (GBA) mutations in patients with Gaucher disease. Hum Mutat. 2002 Apr;19(4):458-9. PMID:11933202 doi:10.1002/humu.9024
- ↑ Filocamo M, Mazzotti R, Stroppiano M, Seri M, Giona F, Parenti G, Regis S, Corsolini F, Zoboli S, Gatti R. Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients. Hum Mutat. 2002 Sep;20(3):234-5. PMID:12204005 doi:10.1002/humu.9058
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Church HJ, Cooper A, Stewart F, Thornton CM, Wraith JE. Homozygous loss of a cysteine residue in the glucocerebrosidase gene results in Gaucher's disease with a hydropic phenotype. Eur J Hum Genet. 2004 Nov;12(11):975-8. PMID:15292921 doi:10.1038/sj.ejhg.5201251
- ↑ Salvioli R, Tatti M, Scarpa S, Moavero SM, Ciaffoni F, Felicetti F, Kaneski CR, Brady RO, Vaccaro AM. The N370S (Asn370-->Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C. Biochem J. 2005 Aug 15;390(Pt 1):95-103. PMID:15826241 doi:BJ20050325
- ↑ Miocic S, Filocamo M, Dominissini S, Montalvo AL, Vlahovicek K, Deganuto M, Mazzotti R, Cariati R, Bembi B, Pittis MG. Identification and functional characterization of five novel mutant alleles in 58 Italian patients with Gaucher disease type 1. Hum Mutat. 2005 Jan;25(1):100. PMID:15605411 doi:10.1002/humu.9301
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Amaral O, Pinto E, Fortuna M, Lacerda L, Sa Miranda MC. Type 1 Gaucher disease: identification of N396T and prevalence of glucocerebrosidase mutations in the Portuguese. Hum Mutat. 1996;8(3):280-1. PMID:8889591 doi:<280::AID-HUMU15>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1996)8:3<280::AID-HUMU15>3.0.CO;2-Z
- ↑ Choy FY, Humphries ML, Ben-Yoseph Y. A novel mutation (V191G) in a German-British type 1 Gaucher disease patient. Mutations in brief no. 131. Online. Hum Mutat. 1998;11(5):411-2. PMID:10206680 doi:<411::AID-HUMU11>3.0.CO;2-2 10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU11>3.0.CO;2-2
- ↑ Wasserstein MP, Martignetti JA, Zeitlin R, Lumerman H, Solomon M, Grace ME, Desnick RJ. Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: identification and expression of a novel acid beta-glucosidase mutation. Am J Med Genet. 1999 Jun 4;84(4):334-9. PMID:10340647
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Miocic S, Filocamo M, Dominissini S, Montalvo AL, Vlahovicek K, Deganuto M, Mazzotti R, Cariati R, Bembi B, Pittis MG. Identification and functional characterization of five novel mutant alleles in 58 Italian patients with Gaucher disease type 1. Hum Mutat. 2005 Jan;25(1):100. PMID:15605411 doi:10.1002/humu.9301
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Choy FY, Humphries ML, Ben-Yoseph Y. Gaucher type 2 disease: identification of a novel transversion mutation in a French-Irish patient. Am J Med Genet. 1998 Jun 16;78(1):92-3. PMID:9637431
- ↑ Sinclair G, Choy FY, Humphries L. A novel complex allele and two new point mutations in type 2 (acute neuronopathic) Gaucher disease. Blood Cells Mol Dis. 1998 Dec;24(4):420-7. PMID:9851895 doi:S1079-9796(98)90210-8
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Seeman PJ, Finckh U, Hoppner J, Lakner V, Liebisch I, Grau G, Rolfs A. Two new missense mutations in a non-Jewish Caucasian family with type 3 Gaucher disease. Neurology. 1996 Apr;46(4):1102-7. PMID:8780099
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009 Jul;132(Pt 7):1783-94. doi: 10.1093/brain/awp044. Epub 2009 Mar 13. PMID:19286695 doi:10.1093/brain/awp044
- ↑ Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul 8;61(1):99-101. PMID:12847165
- ↑ Aharon-Peretz J, Badarny S, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005 Nov 8;65(9):1460-1. Epub 2005 Sep 7. PMID:16148263 doi:10.1212/01.wnl.0000176987.47875.28
- ↑ Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007 Jul;64(7):1056-8. PMID:17620502 doi:10.1001/archneur.64.7.1056
- ↑ Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol. 2008 Mar;65(3):379-82. doi: 10.1001/archneurol.2007.68. PMID:18332251 doi:10.1001/archneurol.2007.68
- ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID:19846850 doi:10.1056/NEJMoa0901281
- ↑ Orwig SD, Tan YL, Grimster NP, Yu Z, Powers ET, Kelly JW, Lieberman RL. Binding of 3,4,5,6-tetrahydroxyazepanes to the acid-beta-glucosidase active site: implications for pharmacological chaperone design for Gaucher disease. Biochemistry. 2011 Dec 13;50(49):10647-57. Epub 2011 Nov 14. PMID:22047104 doi:10.1021/bi201619z
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