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: Susana Ferreira, Alberto Ortiz, Dominique P Germain, Miguel Viana-Baptista, António Caldeira-Gomes, Marta Camprecios, Maria Fenollar-Cortés, Ángel Gallegos-Villalobos, Diego Garcia, José Antonio García-Robles, Jesús Egido, Eduardo Gutiérrez-Rivas, José Antonio Herrero, Sebastián Mas, Raluca Oancea, Paloma Péres, Luis Manuel Salazar-Martín, Jesús Solera-Garcia, Helena Alves, Scott C Garman, João Paulo Oliveira
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 114 Issue 2 Pg. 248-58 (Feb 2015) ISSN: 1096-7206 [Electronic] United States
• PMID: 25468652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Codon
• GLA protein, human
• alpha-Galactosidase

Topics

• Adult
• Alleles
• Amino Acid Substitution
• Codon (genetics)
• Fabry Disease (complications, diagnosis, epidemiology, ethnology)
• Family Health
• Female
• Gene Frequency
• Genotype
• Humans
• Kidney (pathology)
• Male
• Middle Aged
• Molecular Structure
• Mutation
• Phenotype
• alpha-Galactosidase (genetics)