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Mol Genet Metab. 2015 Feb;114(2):248-58. doi: 10.1016/j.ymgme.2014.11.004. Epub 2014 Nov 9.

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies.

Author information

1
Departamento de Genética, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal. Electronic address: susanadg@med.up.pt.
2
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.
3
University of Versailles, UFR des sciences de la santé Simone Veil, Division of Medical Genetics, 78180 Montigny, France. Electronic address: dominique.germain@uvsq.fr.
4
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.
5
Serviço de Nefrologia, Centro Hospitalar de São João, 4200-319 Porto, Portugal. Electronic address: viladoconde@diaverum.com.
6
Servicio de Cardiología, Hospital Moisès Broggi, Sant Joan Despí, Barcelona, Spain.
7
Laboratorio de Genética Clínica, Servicio de Análisis Clínicos, Hospital Clínico Universitario San Carlos, Madrid, Spain. Electronic address: mariadelmar.fenollar@salud.madrid.org.
8
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.
9
Health In Code, Hospital Marítimo de Oza, A Coruña, Spain.
10
Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
11
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.
12
Servicio de Neurología, Hospital Universitario 12 de Octubre, Madrid, Spain.
13
Servicio de Nefrología, Hospital Clínico Universitario San Carlos, Madrid, Spain.
14
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.
15
Laboratorio de Genética Clínica, Servicio de Análisis Clínicos, Instituto de Investigación Sanitaria, Hospital Clínico Universitario San Carlos, Madrid, Spain.
16
Servicio de Cardiología, Hospital Universitario Infanta Leonor, Madrid, Spain.
17
Médico de atención primaria, Calzadilla, Cáceres, Spain.
18
Instituto de Genética Médica y Molecular, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.
19
Centro de Histocompatibilidade do Norte, Porto, Portugal. Electronic address: helena.d.alves@gmail.com.
20
Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA. Electronic address: garman@biochem.umass.edu.
21
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.

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.

KEYWORDS:

Fabry disease; GLA gene; R118C; Variant p.(Arg118Cys); α-Galactosidase A

PMID:
25468652
PMCID:
PMC4423738
DOI:
10.1016/j.ymgme.2014.11.004
[Indexed for MEDLINE]
Free PMC Article

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