Novel <i>PKLR</i> missense mutation (A300P) causing pyruvate kinase deficiency in an Omani Kindred—PK deficiency masquerading as congenital dyserythropoietic anemia

Fawaz, Naglaa; Beshlawi, Ismail; Alqasim, Alauldeen Mudhafar Zubair; Zachariah, Mathew; Russo, Roberta; Andolfo, Immacolata; Gambale, Antonella; Pathare, Anil; Iolascon, Achille

doi:10.1002/ccr3.5315

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…3 Finally, recent investigations have revealed that a significant proportion of patients initially suspected of CDA I or II, based on both hypo-productive anemia and bone marrow morphological characteristics (Figure 2), were ultimately diagnosed with chronic anemia due to enzymatic defects, mainly pyruvate kinase deficiency (PKD) due to PKLR mutations. 12,34 To note, the presence of inadequate reticulocytosis, erythroblasts in peripheral blood, or immature forms at bone marrow examination, are frequently observed in patients with severe PKD. 35 Furthermore, evaluation of the main regulators of iron balance and erythropoiesis, that is, EPO, erythroferrone (ERFE), and hepcidin, showed comparable levels between CDA and PKD patients, 36 thus explaining the misdiagnosis between these conditions.…”

Section: Isolated Formsmentioning

confidence: 99%

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

Russo,

Iolascon,

Andolfo

et al. 2024

Int J Lab Hematology

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Hereditary dyserythropoietic anemias, or congenital dyserythropoietic anemias (CDAs), are rare disorders disrupting normal erythroid lineage development, resulting in ineffective erythropoiesis and monolinear cytopenia. CDAs include three main types (I, II, III), transcription‐factor‐related forms, and syndromic forms. The widespread use of next‐generation sequencing in the last decade has unveiled novel causative genes and unexpected genotype–phenotype correlations. The discovery of the genetic defects underlying the CDAs not only facilitates accurate diagnosis but also enhances understanding of CDA pathophysiology. Notable advancements include identifying a hepatic‐specific role of the SEC23B loss‐of‐function in iron metabolism dysregulation in CDA II, deepening CDIN1 dysfunction during erythroid differentiation, and uncovering a recessive CDA III form associated with RACGAP1 variants. Current treatments primarily rely on supportive measures tailored to disease severity and clinical features. Comparative studies with pyruvate kinase deficiency have illuminated new therapeutic avenues by elucidating iron dyshomeostasis and dyserythropoiesis mechanisms. We herein discuss recent progress in diagnostic methodologies, novel gene discoveries, and enhanced comprehension of CDA pathogenesis and molecular genetics.

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Section: Isolated Formsmentioning

confidence: 99%

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

Russo,

Iolascon,

Andolfo

et al. 2024

Int J Lab Hematology

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PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes

et al. 2023

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Interpreting changes in patient genomes, understanding how viruses evolve and engineering novel protein function all depend on accurately predicting the functional outcomes that arise from amino acid substitutions. To that end, the development of first-generation prediction algorithms was guided by historic experimental datasets. However, these datasets were heavily biased toward substitutions at positions that have not changed much throughout evolution (i.e. conserved). Although newer datasets include substitutions at positions that span a range of evolutionary conservation scores, these data are largely derived from assays that agglomerate multiple aspects of function. To facilitate predictions from the foundational chemical properties of proteins, large substitution databases with biochemical characterizations of function are needed. We report here a database derived from mutational, biochemical, bioinformatic, structural, pathological and computational studies of a highly studied protein family—pyruvate kinase (PYK). A centerpiece of this database is the biochemical characterization—including quantitative evaluation of allosteric regulation—of the changes that accompany substitutions at positions that sample the full conservation range observed in the PYK family. We have used these data to facilitate critical advances in the foundational studies of allosteric regulation and protein evolution and as rigorous benchmarks for testing protein predictions. We trust that the collected dataset will be useful for the broader scientific community in the further development of prediction algorithms. Database URL https://github.com/djparente/PYK-DB

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Novel PKLR missense mutation (A300P) causing pyruvate kinase deficiency in an Omani Kindred—PK deficiency masquerading as congenital dyserythropoietic anemia

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 2 publications

References 22 publications

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

Updates on clinical and laboratory aspects of hereditary dyserythropoietic anemias

PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes

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