Two novel DNA variants associated with glucose-6-phosphate dehydrogenase deficiency found in Argentine pediatric patients

Chaves, Alejandro; Eberle, Silvia Eandi; Defelipe, Lucas A.; Pepe, Carolina; Milanesio, Berenice; Aguirre, Fernando; Fernández, Diego; Turjanski, Adrián; Feliú-Torres, Aurora

doi:10.1016/j.clinbiochem.2016.01.018

Cited by 4 publications

(10 citation statements)

References 12 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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”.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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Summary G6PD deficiency, an enzymopathy affecting 7% of the world population, is caused by over 160 identified amino acid variants in glucose-6-phosphate dehydrogenase (G6PD). The clinical presentation of G6PD deficiency is diverse, likely due to the broad distribution of variants across the protein and the potential for multidimensional biochemical effects. In this study, we use bioinformatic and biochemical analyses to interpret the relationship between G6PD variants and their clinical phenotype. Using structural information and statistical analyses of known G6PD variants, we predict the molecular phenotype of five uncharacterized variants from a reference population database. Through multidimensional analysis of biochemical data, we demonstrate that the clinical phenotypes of G6PD variants are largely determined by a trade-off between protein stability and catalytic activity. This work expands the current understanding of the biochemical underpinnings of G6PD variant pathogenicity, and suggests a promising avenue for correcting G6PD deficiency by targeting essential structural features of G6PD.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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“…In addition, we also include the most recent described mutations for g6pd gene (Table 1). Into the Class I G6PD mutants are the Quilmes (Ser332Phe, exon 9) [52], Merlo (Pro409Gln, exon 10) [52], Herlev [53], and two unnamed mutants (Pro396Arg, exon 10) [54] and (Asn363Ile, exon 10) [55]. Also we incorporate one mutant Class II named G6PD Tunis (Gln307Pro, exon 9) [54] and a Class III G6PD Nefza (Leu323Pro, exon 9) [56] (Figure 5).…”

Section: Molecular Characterization Of G6pd Variantsmentioning

confidence: 99%

“…In some patients, the presence of the most severely affected variants (Class I) as G6PD Zacatecas [37], Hamburg [39], Quilmes [52], Veracruz [37], Merlo [52], Yucatan [37], Tennessee [42], unnamed A1088T [55], and unnamed C1187G [54] mutants presented acute hemolytic anemia and jaundice. Furthermore, the G6PD Taif mutant is unique due that it is the only known deletion in this region closed to the putative G6P-binding domain.…”

Section: Clinical G6pd Deficiencymentioning

confidence: 99%

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

Gómez-Manzo

Marcial-Quino

Vanoye-Carlo

et al. 2016

IJMS

177

147

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Glucose-6-phosphate dehydrogenase (G6PD) is a key regulatory enzyme in the pentose phosphate pathway which produces nicotinamide adenine dinucleotide phosphate (NADPH) to maintain an adequate reducing environment in the cells and is especially important in red blood cells (RBC). Given its central role in the regulation of redox state, it is understandable that mutations in the gene encoding G6PD can cause deficiency of the protein activity leading to clinical manifestations such as neonatal jaundice and acute hemolytic anemia. Recently, an extensive review has been published about variants in the g6pd gene; recognizing 186 mutations. In this work, we review the state of the art in G6PD deficiency, describing 217 mutations in the g6pd gene; we also compile information about 31 new mutations, 16 that were not recognized and 15 more that have recently been reported. In order to get a better picture of the effects of new described mutations in g6pd gene, we locate the point mutations in the solved three-dimensional structure of the human G6PD protein. We found that class I mutations have the most deleterious effects on the structure and stability of the protein.

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“…En los pacientes con AHCNE y una actividad enzimática < 10 %, los estudios moleculares identificaron 4 variantes pertenecientes a la clase I de la OMS, 2 de estas (variantes Merlo y Quilmes) fueron descritas recientemente por nuestro laboratorio. 7 Tres de las variantes encontradas (Merlo, New York y Beverly Hills) se encuentran en el exón 10 y afectan aminoácidos que participan en la dimerización; de esta manera, alteran un paso esencial para la existencia de actividad catalítica. Estas mutaciones rompen los contactos entre las dos subunidades o desorganizan la estructura en la interfase por introducción de aminoácidos con carga eléctrica diferente o de residuos con tamaños distintos.…”

Section: Discussionunclassified

Caracterización fenotípica y genotípica de la deficiencia de glucosa-6-fosfato deshidrogenasa en Argentina. Estudio retrospectivo y descriptivo

Eberle¹,

Pepe²,

Chaves³

et al. 2019

Arch Argent Pediat

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Two novel DNA variants associated with glucose-6-phosphate dehydrogenase deficiency found in Argentine pediatric patients

Cited by 4 publications

References 12 publications

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

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

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

Caracterización fenotípica y genotípica de la deficiencia de glucosa-6-fosfato deshidrogenasa en Argentina. Estudio retrospectivo y descriptivo

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