Glucose-6-phosphate dehydrogenase deficiency in northern Mexico and description of a novel mutation

Abstract

Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common enzyme pathology in humans; it is X-linked inherited and causes neonatal hyperbilirubinaemia, chronic nonspherocytic haemolytic anaemia and drug-induced acute haemolytic anaemia. G6PD deficiency has scarcely been studied in the northern region of Mexico, which is important because of the genetic heterogeneity described in Mexican population. Therefore, samples from the northern Mexico were biochemically screened for G6PD deficiency, and PCR-RFLPs, and DNA sequencing used to identify mutations in positive samples. The frequency of G6PD deficiency in the population was 0.95% (n = 1993); the mutations in 86% of these samples were G6PD A(-202A/376G), G6PDA(-376G/968C) and G6PD Santamaria(376G/542T). Contrary to previous reports, we demonstrated that G6PD deficiency distribution is relatively homogenous throughout the country (P = 0.48336), and the unique exception with high frequency of G6PD deficiency does not involve a coastal population (Chihuahua: 2.4%). Analysis of eight polymorphic sites showed only 10 haplotypes. In one individual we identified a new G6PD mutation named Mexico DF(193A>G) (rs199474830), which probably results in a damaging functional effect, according to PolyPhen analysis. Proteomic impact of the mutation is also described.

Coupling between Protein Stability and Catalytic Activity Determines Pathogenicity of G6PD Variants

“…Reported variants (Benmansour et al, 2013; Chaves et al, 2016; Garcia-Magallanes et al, 2014; Jang et al, 2015; Minucci et al, 2012; Warny et al, 2015) and structural regions were then mapped onto a linear representation of G6PD (Fig. 1A,B) and onto the crystal structure (Fig.…”

“…High-quality missense variants (genotype quality ≥ 20 and depth ≥ 10) in the G6PD transcript ENST00000393564, as of October, 2016, were collected from the ExAC Browser (Lek et al, 2016) and compared with G6PD variants reported in the literature (Benmansour et al, 2013; Chaves et al, 2016; García-Magallanes et al, 2014; Jang et al, 2015; Minucci et al, 2012; Warny et al, 2015). Variants in ExAC that were not previously reported were designated “uncharacterized”.…”

Glucose-6-Phosphate Dehydrogenase: Update and Analysis of New Mutations around the World

“…Furthermore, two double mutants Class II/III G6PD Viangchan + Mahidol (Val291Met, Gly163Ser, exon 9 and 6) and G6PD Viangchan + Union (Val291Met, Arg454Cys, exon 9 and 11) were reported by Nantakomol et al [57] (Figure 5). In addition, two novel mutants: Mexico DF (Thr65Ala, exon 2) [58] and Gaza (Ser179Asn, exon 6) [59] that were not classified according to their residual enzyme activity are considered (Figure 5). Finally, we included a novel mutant that affects the introns named G6PD Qingzhen (IVS5-1G > A) reported by Wei-Liang et al [60].…”

“…Furthermore, Garcia-Magallanes et al [58] reported the presence of a novel mutant G6PD Mexico DF that was identified in a Mexican individual from the northern Mexico; which presents the substitution of 193A > G that changes the amino acid threonine for alanine at position 65 (exon 4) (Figure 5). The Thr65Ala mutation might lead to an unstable coenzyme union site region of the enzyme, due to the combined effect of the suppression of a peptide backbone H-bond and by disrupting the domain packing.…”

Effects of Single and Double Mutants in Human Glucose-6-Phosphate Dehydrogenase Variants Present in the Mexican Population: Biochemical and Structural Analysis

“…In Mexico, the presence of 19 different mutants has been reported, which have been found in several parts of the country, including single nucleotide substitutions (missense variants) G6PD A+ (Asn126Asp), G6PD San Luis Potosi (Asn126Tyr), and Guadalajara (Arg387Cys), which have given rise to the double mutant G6PD Mount Sinai (Asn126Asp + Arg387Cys) [13,14]. It is important to note that the Class II G6PD San Luis Potosi and two Class I G6PDs, Guadalajara and Mount Sinai variants, have not been functionally and biochemically characterized.…”