{
    "abstract": "Fabry disease (FD) is a rare X-linked storage disorder resulting from the deficient activity of the lysosomal hydrolase \u03b1-galactosidase A (\u03b1-Gal A). Here we describe a 23-year-old man with FD possessing a novel mutation in the GLA gene, the evaluation of his family, and the functional characterization of the novel variant.\nTwo generations of a family were screened for FD by clinical symptoms and low enzymatic activity. This step was followed by DNA sequencing that showed a novel GLA missense mutation. To confirm the pathogenicity potential of the mutation, we employed site-directed polymerase chain reaction mutagenesis. GLA wild-type and mutant plasmids were transfected into mammalian cells; RNA and proteins were extracted for expression and analysis of enzymatic activity.\nThe patient presents the variant p.Asn34Asp in the GLA and had several manifestations of FD since adolescence. The investigation of the deficiency of \u03b1-Gal A was initiated due to stage 4 of chronic kidney disease. All family members carrying the novel mutation presented early symptoms, including index case's mother, who received a renal transplant when she was 35 years old. In silico and in vitro analysis confirmed the pathogenic potential of the mutation p.Asn34Asp showing that the enzyme had only 4% of residual activity due to protein misfolding. The ability of the pharmacological chaperone 1-deoxygalactonojirimycin to recover the mutant was confirmed, producing 37.5% of residual activity.\nIn this work, we present a novel missense mutation in GLA that leads to the production of a catalytically competent \u03b1-Gal A, which is degraded before its delivery to the lysosome, promoting severe manifestations of FD, with a very similar disease course in affected men and women.",
    "authors": [
        {
            "affiliation": "Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Patr\u00edcia",
            "initials": "P",
            "lastname": "Varela"
        },
        {
            "affiliation": "Division of Nephrology, Department of Medicine, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Gianna",
            "initials": "G",
            "lastname": "Mastroianni Kirsztajn"
        },
        {
            "affiliation": "Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Henrique",
            "initials": "H",
            "lastname": "Ferrer"
        },
        {
            "affiliation": "Reference Center in Inborn Errors of Metabolism, Department of Pediatrics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Carolina",
            "initials": "C",
            "lastname": "Aranda"
        },
        {
            "affiliation": "Reference Center in Inborn Errors of Metabolism, Department of Pediatrics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Krissia",
            "initials": "K",
            "lastname": "Wallbach"
        },
        {
            "affiliation": "Division of Nephrology, Department of Medicine, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Gustavo",
            "initials": "G",
            "lastname": "Ferreira da Mata"
        },
        {
            "affiliation": "Division of Nephrology, Department of Medicine, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Luiz A",
            "initials": "LA",
            "lastname": "Moura"
        },
        {
            "affiliation": "Division of Nephrology, Department of Medicine, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "S\u00edlvia R",
            "initials": "SR",
            "lastname": "Moreira"
        },
        {
            "affiliation": "Reference Center in Inborn Errors of Metabolism, Department of Pediatrics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Carmen",
            "initials": "C",
            "lastname": "Mendes"
        },
        {
            "affiliation": "Reference Center in Inborn Errors of Metabolism, Department of Pediatrics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Marco A",
            "initials": "MA",
            "lastname": "Curiati"
        },
        {
            "affiliation": "Reference Center in Inborn Errors of Metabolism, Department of Pediatrics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil.",
            "firstname": "Ana Maria",
            "initials": "AM",
            "lastname": "Martins"
        },
        {
            "affiliation": "Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil, jbpesquero@gmail.com.",
            "firstname": "Jo\u00e3o",
            "initials": "J",
            "lastname": "Bosco Pesquero"
        }
    ],
    "conclusions": "In this work, we present a novel missense mutation in GLA that leads to the production of a catalytically competent \u03b1-Gal A, which is degraded before its delivery to the lysosome, promoting severe manifestations of FD, with a very similar disease course in affected men and women.",
    "copyrights": "\u00a9 2019 S. Karger AG, Basel.",
    "doi": "10.1159/000503998",
    "journal": "Nephron",
    "keywords": [
        "Chronic renal failure",
        "End-stage kidney disease",
        "Fabry disease",
        "Kidney transplantation",
        "Nephropathy",
        "Neuropathy",
        "Pharmacological chaperone"
    ],
    "methods": null,
    "publication_date": "2019-10-31",
    "pubmed_id": "31665721",
    "results": "The patient presents the variant p.Asn34Asp in the GLA and had several manifestations of FD since adolescence. The investigation of the deficiency of \u03b1-Gal A was initiated due to stage 4 of chronic kidney disease. All family members carrying the novel mutation presented early symptoms, including index case's mother, who received a renal transplant when she was 35 years old. In silico and in vitro analysis confirmed the pathogenic potential of the mutation p.Asn34Asp showing that the enzyme had only 4% of residual activity due to protein misfolding. The ability of the pharmacological chaperone 1-deoxygalactonojirimycin to recover the mutant was confirmed, producing 37.5% of residual activity.",
    "title": "Functional Characterization and Pharmacological Evaluation of a Novel GLA Missense Mutation Found in a Severely Affected Fabry Disease Family.",
    "xml": "<Element 'PubmedArticle' at 0x788504100b80>"
}