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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2010-2-3
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pubmed:abstractText |
Fabry Disease (FD) is an X-linked multisystemic lysosomal disorder caused by mutations of alpha-galactosidase (GLA) gene. Only a few of the 450 genetic lesions identified so far have been characterised by in vitro expression studies. Thus the significance of newly identified GLA nucleotide variants in FD patients which lead to alpha-galactosidase (GAL-A) amino acid substitutions or intronic changes can be uncertain. We identified three GLA mutations, c.155G>A (p.C52Y), c.548G>C (p.G183A), c.647A>G (p.Y216C) in as many individuals (two male; one female) and performed in vitro expression studies and Western blot analysis in order to clarify their functional effects. Reduced GAL-A activity and normal or partially reduced mutant proteins were present in all overexpressed mutant systems in which three-dimensional structural analysis showed that the active site was not directly involved. We hypothesize that the three new mutations affect the GAL-A protein, leading to conformational FD. When mutant proteins overexpressed in COS-1 cells and in patients' lymphocytes were tested in the presence of the 1-deoxygalactonojirimicin (DGJ) chaperone, the p.G183A and p.Y216C systems showed increased GAL-A enzyme activities and protein stabilisation while p.C52Y was not responsive. We underline that genetic, biochemical and functional studies are helpful in clarifying the consequences of the missense genetic lesions detected in FD. ERT is the elective therapy for Fabry patients, but it is not always possible to issue the enzyme's active form in all involved organs. Our study endorses the hypothesis that an active site-specific chemical chaperone, which could be administered orally, might be effective in treating GAL-A conformational defects.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0006-3002
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pubmed:author |
pubmed-author:AntuzziDD,
pubmed-author:CaciottiAA,
pubmed-author:CarraresiLL,
pubmed-author:CavicchiCC,
pubmed-author:DonatiM AMA,
pubmed-author:FeriozziSS,
pubmed-author:FiloniCC,
pubmed-author:GarmanS CSC,
pubmed-author:GuerriniRR,
pubmed-author:MorroneAA,
pubmed-author:PariniRR,
pubmed-author:PoisettiPP,
pubmed-author:ZammarchiEE,
pubmed-author:ZampettiAA
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pubmed:copyrightInfo |
Copyright 2009 Elsevier B.V. All rights reserved.
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pubmed:issnType |
Print
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pubmed:volume |
1802
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
247-52
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pubmed:dateRevised |
2011-7-26
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pubmed:meshHeading |
pubmed-meshheading:19941952-Animals,
pubmed-meshheading:19941952-COS Cells,
pubmed-meshheading:19941952-Cercopithecus aethiops,
pubmed-meshheading:19941952-Chromosome Mapping,
pubmed-meshheading:19941952-DNA,
pubmed-meshheading:19941952-DNA Primers,
pubmed-meshheading:19941952-Enzyme Replacement Therapy,
pubmed-meshheading:19941952-Fabry Disease,
pubmed-meshheading:19941952-Female,
pubmed-meshheading:19941952-Humans,
pubmed-meshheading:19941952-Male,
pubmed-meshheading:19941952-Models, Molecular,
pubmed-meshheading:19941952-Molecular Conformation,
pubmed-meshheading:19941952-Mutagenesis, Site-Directed,
pubmed-meshheading:19941952-Mutation,
pubmed-meshheading:19941952-Phenotype,
pubmed-meshheading:19941952-Protein Conformation,
pubmed-meshheading:19941952-Transfection,
pubmed-meshheading:19941952-X Chromosome,
pubmed-meshheading:19941952-alpha-Galactosidase
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pubmed:year |
2010
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pubmed:articleTitle |
Functional studies of new GLA gene mutations leading to conformational Fabry disease.
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pubmed:affiliation |
Metabolic and Muscular Unit, Clinic of Pediatric Neurology, A.O.U Meyer, Florence, Italy.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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