Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002986 (Fabry)
 5,646 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked agammaglobulinaemia (XLA) is an inherited disorder characterised by a lack of circulating B-cells and antibodies. While the gene involved in XLA has not yet been identified, the locus for the disorder is tightly linked to the polymorphic marker DXS178, which maps to Xq22. Fabry disease is an X-linked recessive disorder caused by a deficiency in the lysosomal enzyme alpha-galactosidase A. The gene encoding this enzyme has been characterized and also maps to Xq22. Using pulsed field gel electrophoresis we have constructed a long-range restriction map that shows that the alpha-galactosidase A gene (GLA) and DXS178 lie no more than 140 kb apart on a stretch of DNA containing a number of putative CpG islands. We have also isolated yeast artificial chromosome (YAC) clones that confirm this physical linkage. The localisation of DXS178 near the alpha-galactosidase A gene will facilitate carrier detection in Fabry families using restriction fragment length polymorphism (RFLP) analysis. The identification of a number of CpG islands near DXS178 also provides candidate locations for the gene responsible for XLA.
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PMID:Physical mapping shows close linkage between the alpha-galactosidase A gene (GLA) and the DXS178 locus. 810 5

Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from lesions in the alpha-galactosidase A gene leading to deficient or absent activity of the lysosomal hydrolase. To facilitate the detection of rearrangements in this 14-kb gene, a method was developed for the PCR amplification of all seven exons from genomic DNA in a single multiplex reaction. The entire coding region and all the intron/exon boundaries were amplified as four products. Application of this method permitted the detection of all five partial deletions previously identified by Southern analysis. This rapid method can be used to identify gene rearrangements in affected hemizygotes and determine heterozygosity for at risk females in families with Fabry disease.
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PMID:Fabry disease: detection of gene rearrangements in the human alpha-galactosidase A gene by multiplex PCR amplification. 831 86

The alpha-galactosidase A gene (GALA), which is deficient in males with Anderson-Fabry disease, is shown to be remarkably polymorphic in the 5' untranslated region. GALA contains seven exons. The first exon contains 60 bp of 5' untranslated sequence before the methionine initiation codon. Single strand conformation polymorphism (SSCP) screening has shown three polymorphic variants from the published sequence within the 60 base pairs. The sequence changes involved are C to T at -10, G to A at -12 (which removes an MspI site), and G to A at -30 (which removes a SacII site). The combined frequency of these is 10%. A further insertion-deletion polymorphism is detected by SSCP of a 400 bp fragment including exon 3. Both polymorphisms can be easily detected using small polyacrylamide gels and ethidium bromide staining. Nine of 20 women were informative for one of these polymorphisms and this simple SSCP analysis should be of great assistance in family studies of Anderson-Fabry disease. Such a high level of polymorphism has not been previously reported in the 5' untranslated region of a human gene and is unusual in any such short stretch of DNA.
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PMID:Sequence variations in the first exon of alpha-galactosidase A. 841 Oct 52

A Japanese male patient with Fabry disease who had no activity of the lysosomal hydrolase alpha-galactosidase A (alpha-GalA) and female members of his family were analyzed. We cloned a cDNA encoded the mutant alpha-GalA, determined its nucleotide sequence, and found two nucleotide differences between the mutant and the wild-types cDNAs. The one difference, a C-to-T transition at nucleotide number 118, resulted in an amino acid substitution of Pro-40 by Ser. A transient expression assay demonstrated that this missense mutation was the cause of the deficiency of alpha-GalA activity in the patient. Gene analysis of the patient's family by PCR and subsequent sequencing demonstrated that all females were heterozygotes.
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PMID:[Molecular genetic analysis of a Japanese family with Fabry disease]. 841 4

Fabry's disease is a rare, inherited, X-linked metabolic storage disease with ceramide hexoside due to alpha-galactosidase A deficiency. Patients with typical Fabry's disease usually present with several clinical manifestations of corneal dystrophy, neurologic abnormalities, cardiovascular disease, heavy proteinuria, and characteristic cutaneous angiokeratoma. However, atypical Fabry's disease with oligosymptomatic phenotype presents with symptoms restricted solely to cardiocytes or kidney and might be diagnosed by chance during a routine endomyocardial or renal biopsy examination. In this article, we report a case of Fabry's disease incidentally diagnosed in a 34-year-old man who presented with intermittent trace or 1(+) proteinuria only. This patient had no history of renal disease in any other family member. A renal biopsy to evaluate trace proteinuria revealed histologic and ultrastructural findings compatible with Fabry's disease. Subsequent to the renal biopsy, a skin biopsy on a few initially unrecognized, scattered, dark-pinkish scrotal papules showed typical angiokeratoma. A biochemical enzymatic assay of alpha-galactosidase in urine and plasma revealed a markedly decreased enzyme level in the hemizygous range.
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PMID:Atypical Fabry's disease. An oligosymptomatic variant. 855 52

A point mutation in exon 6 of the alpha-galactosidase A gene (alpha-GAL A) was found in a Japanese hemizygous male without typical manifestations of Fabry disease other than renal involvement. This 45-year-old man developed moderate proteinuria and was diagnosed with Fabry disease on the basis of renal histologic findings and prominent decreases in alpha-GAL A activity in his plasma, urine, leukocytes, and skin fibroblasts. Determination of the cDNA sequence of his alpha-GAL A gene revealed substitution of a G to A in codon 301, resulting in a glutamine rather than an arginine residue. Our case is unique in that this patient only demonstrated renal manifestations while all other reported patients with atypical Fabry disease, including a case with the identical point mutation, present with a cardiomyopathy. Direct DNA sequencing of exon 6 and measurement of alpha-GAL A activity among the patient's family confirmed that the mutation was transmitted from his mother.
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PMID:Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy. 873 59

Fabry disease is an X-linked metabolic disorder due to a deficiency of alpha-galactosidase A (alpha-gal A; EC 3.2.1.22). Patients accumulate glycosphingolipids with terminal alpha-galactosyl residues that come from intracellular synthesis, circulating metabolites, or from the biodegradation Of senescent cells. Patients eventually succumb to renal, cardio-, or cerebrovascular disease. No specific therapy exists. One possible approach to ameliorating this disorder is to target corrective gene transfer therapy to circulating hematopoietic cells. Toward this end, an amphotropic virus-producer cell line has been developed that produces a high titer (>10(6) i.p. per ml) recombinant retrovirus constructed to transduce and correct target cells. Virus-producer cells also demonstrate expression of large amounts of both intracellular and secreted alpha-gal A. To examine the utility of this therapeutic vector, skin fibroblasts from Fabry patients were corrected for the metabolic defect by infection with this recombinant virus and secreted enzyme was observed. Furthermore, the secreted enzyme was found to be taken up by uncorrected cells in a mannose-6-phosphate receptor-dependent manner. In related experiments, immortalized B cell lines from Fabry patients, created as a hematologic delivery test system, were transduced. As with the fibroblasts, transduced patient B cell lines demonstrated both endogenous enzyme correction and a small amount of secretion together with uptake by uncorrected cells. These studies demonstrate that endogenous metabolic correction in transduced cells, combined with secretion, may provide a continuous source of corrective material in trans to unmodified patient bystander cells (metabolic cooperativity).
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PMID:Correction in trans for Fabry disease: expression, secretion and uptake of alpha-galactosidase A in patient-derived cells driven by a high-titer recombinant retroviral vector. 875 77

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of alpha-galactosidase A (alpha-gal; EC 3.2.1.22). In the past, it has been difficult to give an unequivocal diagnosis of carrier status in Fabry disease because of the overlap between normal and heterozygote enzyme levels. To facilitate rapid and accurate carrier and hemizygote detection, a mutation detection strategy was devised to determine the lesion in our Fabry disease patients. The seven alpha-gal exons and adjacent intron boundaries from a representative member of each kindred were PCR amplified and analysed for the presence of sequence alterations by single-stranded conformation polymorphism (SSCP) analysis followed by PCR sequencing. Here we report the use of this strategy in the detection and analysis of the causative mutations in 9 patients with classic severe Fabry disease. Three deletions of 1-, 2-, and 3-bp (987delC, 717delAA, and delta E358), five amino acid substitutions (C52R, G128E, P205T, M284T, and N298K) and a mutation that affects the initiating methionine (M1I) were found in these patients. Counting a previously reported mutation, this strategy has now successfully detected all the Fabry disease mutations present in the 10 kindreds that have been analysed.
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PMID:A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene. 880 34

We describe the molecular characterization of a novel, in-frame deletion that is located in exon 7 of the alpha-galactosidase A gene in a patient with Fabry's disease. The 3-bp deletion we identified, besides the typical severe clinical features, also expresses diffuse facial telangiectasias, which is a new cutaneous marker of Fabry's disease.
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PMID:Novel trinucleotide deletion in Fabry's disease. 883 44

The introduction of molecular therapy through the delivery of nucleic acids either as oligonucleotides or genetic constructs holds enormous promise for the treatment of renal disease. Significant barriers remain, however, before successful organ-specific molecular therapy can be applied to the kidney. These include the development of methods to target the kidney selectively, the definition of vectors that transduce renal tissue, the identification of appropriate molecular targets, the development of constructs that are regulated and expressed for long periods of time, the demonstration of efficacy in vivo, and the demonstration of safety in humans. As the genetic and pathophysiologic basis of renal disease is clarified, obvious targets for therapy will be defined, for example, polycystin in polycystic kidney disease, human immunodeficiency virus (HIV) type 1 in HIV-associated nephropathy, alpha-galactosidase A in Fabry's disease, insulin in diabetic nephropathy, and the "minor" collagen IV chains in Alport's syndrome. In addition, several potential mediators of progressive renal disease may be amenable to molecular therapeutic strategies, such as interleukin-6, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta(TGF-beta). To test the in vivo efficacy of molecular therapy, appropriate animal models for these disease states must be developed, an area that has received too little attention. For the successful delivery of genetic constructs to the kidney, both viral and nonviral vector systems will be required. The kidney has a major advantage over other solid organs since it is accessible by many routes, including intrarenal artery infusion, retrograde delivery through the uroexcretory pathways, and ex vivo during transplantation. To further restrict expression to the kidney, tropic vectors and tissue-specific promoters also must be developed. For the purpose of inhibition of endogenous or exogenous genes, current therapeutic modalities include the delivery of antisense oligodeoxynucleotides or ribozymes. For these approaches to succeed, we must gain a much better understanding of the nature of their transport into the kidney, requirements for specificity, and in vivo mechanisms of action. The danger of a rush to clinical application is that superficial approaches to these issues will likely fail and enthusiasm will be lost for an area that should be one of the most exciting developments in therapeutics in the next decade.
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PMID:Molecular therapy for renal diseases. 884 Sep 36


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