title: The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies.
abstract: Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands' close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for "rare" condition.
authors.affiliation: Departamento de Genética, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal. Electronic address: susanadg@med.up.pt.
authors.forename: Susana
authors.initials: S
authors.lastname: Ferreira
authors.affiliation: Servicio de Nefrología, Instituto de Investigación Sanitaria IIS-Fundación Jiménez Diaz, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: aortiz@fjd.es.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: University of Versailles, UFR des sciences de la santé Simone Veil, Division of Medical Genetics, 78180 Montigny, France. Electronic address: dominique.germain@uvsq.fr.
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Germain
authors.affiliation: Serviço de Neurologia, Hospital Egas Moniz, Centro Hospitalar Lisboa Ocidental, Centro de Estudo de Doenças Crónicas (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal. Electronic address: mvianabaptista@fcm.unl.pt.
authors.forename: Miguel
authors.initials: M
authors.lastname: Viana-Baptista
authors.affiliation: Serviço de Nefrologia, Centro Hospitalar de São João, 4200-319 Porto, Portugal. Electronic address: viladoconde@diaverum.com.
authors.forename: António
authors.initials: A
authors.lastname: Caldeira-Gomes
authors.affiliation: Servicio de Cardiología, Hospital Moisès Broggi, Sant Joan Despí, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Camprecios
authors.affiliation: Laboratorio de Genética Clínica, Servicio de Análisis Clínicos, Hospital Clínico Universitario San Carlos, Madrid, Spain. Electronic address: mariadelmar.fenollar@salud.madrid.org.
authors.forename: Maria
authors.initials: M
authors.lastname: Fenollar-Cortés
authors.affiliation: Servicio de Nefrología, Instituto de Investigación Sanitaria IIS-Fundación Jiménez Diaz, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: angelgallegos.nefro@gmail.com.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Gallegos-Villalobos
authors.affiliation: Health In Code, Hospital Marítimo de Oza, A Coruña, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Garcia
authors.affiliation: Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: García-Robles
authors.affiliation: Servicio de Nefrología, Instituto de Investigación Sanitaria IIS-Fundación Jiménez Diaz, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: jegido@fjd.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: Servicio de Neurología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gutiérrez-Rivas
authors.affiliation: Servicio de Nefrología, Hospital Clínico Universitario San Carlos, Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Herrero
authors.affiliation: Servicio de Nefrología, Instituto de Investigación Sanitaria IIS-Fundación Jiménez Diaz, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: smas@fjd.es.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Mas
authors.affiliation: Laboratorio de Genética Clínica, Servicio de Análisis Clínicos, Instituto de Investigación Sanitaria, Hospital Clínico Universitario San Carlos, Madrid, Spain.
authors.forename: Raluca
authors.initials: R
authors.lastname: Oancea
authors.affiliation: Servicio de Cardiología, Hospital Universitario Infanta Leonor, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Péres
authors.affiliation: Médico de atención primaria, Calzadilla, Cáceres, Spain.
authors.forename: Luis Manuel
authors.initials: LM
authors.lastname: Salazar-Martín
authors.affiliation: Instituto de Genética Médica y Molecular, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Solera-Garcia
authors.affiliation: Centro de Histocompatibilidade do Norte, Porto, Portugal. Electronic address: helena.d.alves@gmail.com.
authors.forename: Helena
authors.initials: H
authors.lastname: Alves
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA. Electronic address: garman@biochem.umass.edu.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Garman
authors.affiliation: Departamento de Genética, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal; Serviço de Nefrologia, Centro Hospitalar de São João, 4200-319 Porto, Portugal; Consulta de Genética Médica, Centro Hospitalar de São João, 4200-319 Porto, Portugal. Electronic address: jpo@med.up.pt.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Oliveira
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D003062:Codon / Q000235:genetics; D000795:Fabry Disease / Q000150:complications / Q000175:diagnosis* / Q000453:epidemiology / Q000208:ethnology*; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009154:Mutation; D010641:Phenotype; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D003062:Codon; C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: Fabry disease; GLA gene; R118C; Variant p.(Arg118Cys); α-Galactosidase A