Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene

Abstract

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.

Systematic DNA Study for Fabry Disease in the End Stage Renal Disease Patients from a Southern Italy Area

“…Of interest, we also observed that as much as the 22.4% of the whole dialysis population displays intronic polymorphisms of the GLA gene [20] which is a prevalence significantly higher than that registered in the corresponding general population. Even though some studies try to associate these intronic mutations in GLA gene with Fabry disease [28], the involvement of intronic mutation in Fabry disease remains unclear.…”

“…In 55 of 227 patients (24.2%), we found mutations in non-coding GLA regions, the most of those are grouped in aplotypes (Table 3) [20]. In all of these patients, the analysis of enzymatic activity was inside the normal range.…”

The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

“…ncbi.nlm.nih.gov/nuccore/NM_000169.2; National Library of Medicine, Bethesda, MD, USA). Three single nucleotide polymorphisms (SNPs) respectively identified by reference numbers rs2071225, rs3027585 and rs3027584 at the NCBI SNP database (dbSNP, http://www.ncbi.nlm.nih.gov/snp/), which result from cytosine-to-thymine (C>T) or adenineto-guanine (G>A) transitions at cDNA nucleotide positions c.-10(C>T), c.-12(G>A) and c.-30(G>A), counting backwards from the translation initiation codon, are relatively common in several ethnically different populations (Davies et al 1993;Saifudeen et al 1995;Wu et al 2011;Ferri et al 2012), including the Portuguese (Oliveira et al 2008a). The dbSNP lists three additional GLA 5 0 UTR SNPs, at positions c.-8(C>G), c.-18(T>C) and c.-105(A>G), respectively identified as rs371291716, rs545597063 and rs3027583, but these variants have never been reported in the Portuguese population.…”

Phenotype and Genotype Characterization and Twin Association in Patients with Anderson-Fabry Cardiomyopathy

“…To date, more than 600 pathogenetic mutations (missense, nonsense, and splice site point mutations and 'short length' rearrangements such as deletions and duplications) and up to 14 DNA polymorphisms have been reported [2] .…”