Case report: Identification of a rare homozygous missense variant in the PKLR gene reported for the first time in transfusion-dependent Saudi Patient
DOI:
https://doi.org/10.22317/jcms.v9i3.1354Keywords:
PKD, Heterogeneity, β-thalassemia, consanguineous family, PKLR geneAbstract
Red cell pyruvate kinase deficiency is one of the most common erythrocytic glycolytic pathway defects connected with congenital non-spherocytic anemia. The condition inherited as an autosomal recessive Mendelian trait is caused by mutations in the PKLR gene located on chromosome 1q21. Pyruvate kinase enzyme is crucial in the energy-producing glycolysis pathway that provides red blood cells with the primary source of energy (ATP). We report here a case of a Saudi female patient that was initially diagnosed at a few months old with beta-thalassemia major and was treated with regular blood transfusions and iron overload management. At the time of our sample collection, the patient was recently transferred to King Abdul Aziz University Hospital. Genetic testing was performed to identify the disease-contributing variant of beta-thalassemia using TaqMan genotyping of six common beta-thalassemia variants (negative results). NGS targeted HBB gene sequencing which did not reveal any related variants. MLPA was performed to rule out alpha thalassemia diagnosis. The use of whole genome sequencing revealed a rare missense variant in the PKLR gene c.1015G>A (D339N) in a homozygous state that correlates to her severe phenotype. Documenting this incident will aid medical staff in providing appropriate care to similar cases and highlights the importance of following up with the diagnosis investigation process to minimize misdiagnosis incidences.
References
Bianchi, P. and E. Fermo, Molecular heterogeneity of pyruvate kinase deficiency. Haematologica, 2020. 105(9): p. 2218-2228.
Selwyn, J.G. and J.V. Dacie, Autohemolysis and Other Changes Resulting from the Incubation in Vitro of Red Cells from Patients with Congenital Hemolytic Anemia. Blood, 1954. 9(5): p. 414-438.
Valentine, W.N., A speciffic erythrocyte glycolytic enzymedefect (pyruvate kinase) in three subjects with congenital nonspherocytic hemolytic anemia. Trans Ass Amer Physicians, 1961. 74: p. 100-110.
Tanaka, K.R., W.N. Valentine, and S. Miwa, Pyruvate kinase (PK) deficiency hereditary nonspherocytic hemolytic anemia. Blood, 1962. 19: p. 267-95.
De Gruchy, G.C., et al., Nonspherocytic congenital hemolytic anemia. Blood, 1960. 16: p. 1371-97.
Grace, R.F. and W. Barcellini, Management of pyruvate kinase deficiency in children and adults. Blood, 2020. 136(11): p. 1241-1249.
Al-Samkari, H., et al., The variable manifestations of disease in pyruvate kinase deficiency and their management. Haematologica, 2020. 105(9): p. 2229-2239.
Roy, M.K., et al., Red Blood Cell Metabolism in Pyruvate Kinase Deficient Patients. Frontiers in Physiology, 2021. 12.
Porter, M.L. and B.L. Dennis, Hyperbilirubinemia in the term newborn. Am Fam Physician, 2002. 65(4): p. 599-606.
Grace, R.F., et al., Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study. Blood, 2018. 131(20): p. 2183-2192.
Secrest, M.H., et al., Prevalence of pyruvate kinase deficiency: A systematic literature review. Eur J Haematol, 2020. 105(2): p. 173-184.
Canu, G., et al., Red blood cell PK deficiency: An update of PK-LR gene mutation database. Blood Cells Mol Dis, 2016. 57: p. 100-9.
Bianchi, et al., Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency. American Journal of Hematology, 2019. 94(1): p. 149-161.
Agarwal, A.M., et al., Clinical utility of next-generation sequencing in the diagnosis of hereditary haemolytic anaemias. Br J Haematol, 2016. 174(5): p. 806-14.
Roy, N.B., et al., A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias. Br J Haematol, 2016. 175(2): p. 318-330.
Wooderchak-Donahue, W.L., et al., A direct comparison of next generation sequencing enrichment methods using an aortopathy gene panel- clinical diagnostics perspective. BMC Med Genomics, 2012. 5: p. 50.
Sun, Y., et al., Next-generation diagnostics: gene panel, exome, or whole genome? Hum Mutat, 2015. 36(6): p. 648-55.
Kim, Y., J. Park, and M. Kim, Diagnostic approaches for inherited hemolytic anemia in the genetic era. Blood Res, 2017. 52(2): p. 84-94.
Rehman, A.U., et al., A novel homozygous missense variant p.D339N in the PKLR gene correlates with pyruvate kinase deficiency in a Pakistani family: a case report. J Med Case Rep, 2022. 16(1): p. 66.
Chen, M., J. Zhang, and J.L. Manley, Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA. Cancer Res, 2010. 70(22): p. 8977-80.
P., B., et al., Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency. Am J Hematol, 2019. 94(1): p. 149-161.
Schormann, N., et al., An overview of structure, function, and regulation of pyruvate kinases. Protein Sci, 2019. 28(10): p. 1771-1784.
Valentini, G., et al., Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. J Biol Chem, 2002. 277(26): p. 23807-14.
Zanella, A., et al., Pyruvate kinase deficiency: The genotype-phenotype association. Blood Reviews, 2007. 21(4): p. 217-231.
Murakami, K. and M. Yoshino, Zinc inhibition of pyruvate kinase of M-type isozyme. Biometals, 2017. 30(3): p. 335-340.
Wallace, A.C., R.A. Laskowski, and J.M. Thornton, LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng, 1995. 8(2): p. 127-34.
Ben, A., et al., ConSurf-DB: An accessible repository for the evolutionary conservation patterns of the majority of PDB proteins. Protein Sci, 2020. 29(1): p. 258-267.
Lu, S., et al., CDD/SPARCLE: the conserved domain database in 2020. Nucleic Acids Res, 2020. 48(D1): p. D265-d268.
Zanella, A., et al., Molecular Characterization of PK-LR Gene in Pyruvate Kinase–Deficient Italian Patients. Blood, 1997. 89(10): p. 3847-3852.
Zanella, A., et al., Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol, 2005. 130(1): p. 11-25.
Valentini, G., et al., The allosteric regulation of pyruvate kinase. J Biol Chem, 2000. 275(24): p. 18145-52.
Mattevi, A., et al., Crystal structure of Escherichia coli pyruvate kinase type I: molecular basis of the allosteric transition. Structure, 1995. 3(7): p. 729-41.
Mohamed, D.S., et al., Sesame oil ameliorates valproic acid-induced hepatotoxicity in mice: integrated in vivo-in silico study. J Biomol Struct Dyn, 2022: p. 1-21.
Ng, P.C. and S. Henikoff, SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res, 2003. 31(13): p. 3812-4.
Bromberg, Y. and B. Rost, SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res, 2007. 35(11): p. 3823-35.
Capriotti, E. and P. Fariselli, PhD-SNPg: a webserver and lightweight tool for scoring single nucleotide variants. Nucleic Acids Res, 2017. 45(W1): p. W247-W252.
Reva, B., Y. Antipin, and C. Sander, Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res, 2011. 39(17): p. e118.
Thomas, P.D., et al., PANTHER: a library of protein families and subfamilies indexed by function. Genome Res, 2003. 13(9): p. 2129-41.
Pejaver, V., et al., Inferring the molecular and phenotypic impact of amino acid variants with MutPred2. Nat Commun, 2020. 11(1): p. 5918.
Adzhubei, I.A., et al., A method and server for predicting damaging missense mutations. Nat Methods, 2010. 7(4): p. 248-9.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Journal of Contemporary Medical Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
