title: Molecular and clinical studies in five index cases with novel mutations in the GLA gene.
abstract: Fabry disease is a metabolic and lysosomal storage disorder caused by the functional defect of the α-galactosidase A enzyme; this defect is due to mutations in the GLA gene, that is composed of seven exons and is located on the long arm of the X-chromosome (Xq21-22). The enzymatic deficit is responsible for the accumulation of glycosphingolipids in lysosomes of different cellular types, mainly in those ones of vascular endothelium. It consequently causes a cellular and microvascular dysfunction. In this paper, we described five novel mutations in the GLA gene, related to absent enzymatic activity and typical manifestations of Fabry disease. We identified three mutations (c.846_847delTC, p.E341X and p.C382X) that lead to the introduction of a stop codon in positions 297, 341 and 382. Moreover we found a missense mutation (p.R227P) in the exon 5 of the GLA gene and a single point mutation (c.639+5 G>T) occurring five base pairs beyond the end of the exon 4. These mutations have never been found in our group of healthy control subjects >2300. The studied patients presented some clinical manifestations, such as cornea verticillata, hypo-anhidrosis, left ventricular hypertrophy, cerebrovascular disorders and renal failure, that, considering the null enzymatic activity, suggest that the new mutations reported here are related to the classic form of Fabry disease. The identification of novel mutations in patients with symptomatology referable to FD increases the molecular knowledge of the GLA gene and it gives clinicians an important support for the proper diagnosis of the disease.
authors.affiliation: Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy. Electronic address: zizzo@ibim.cnr.it.
authors.forename: Carmela
authors.initials: C
authors.lastname: Zizzo
authors.affiliation: Clinical Echocardiography, Research and Training European CVI Laboratory, Cardio-Thorax-Vascular Transplant Department, Policlinic "G. Rodolico" of University, Catania, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Monte
authors.affiliation: Department of Public Health, Section of Nephrology, Federico II University of Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.affiliation: Internal Medicine, Nephrology and Dialysis Unit, Department of Clinical and Experimental Medicine, University of Catania, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fatuzzo
authors.affiliation: Department of Public Health, Section of Nephrology, Federico II University of Naples, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Riccio
authors.affiliation: Institute of Neurological Sciences (ISN), National Research Council, Catania, Italy.
authors.forename: Margherita Stefania
authors.initials: MS
authors.lastname: Rodolico
authors.affiliation: Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Colomba
authors.affiliation: Operative Unit of Ophthalmology, University of Catania, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Uva
authors.affiliation: Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cammarata
authors.affiliation: Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy; Department of Biopathology and Medical Biotechnology, University of Palermo, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Alessandro
authors.affiliation: Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iemolo
authors.affiliation: Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Duro
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D000795:Fabry Disease / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: Alpha-galactosidase A; Fabry disease; c.639+5G>T; c.846_847delTC; p.C382X; p.E341X; p.R227P