Identification and in silico characterization of a novel PKLR genotype in a Turkish newborn
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Identification and in silico characterization of a novel PKLR genotype in a Turkish newborn Giulia Canu1 · Elisa De Paolis1 · Benedetta Righino2 · Giorgia Mazzuccato1 · Giulio De Paolis1 · Ettore Capoluongo3 · Maria Cristina De Rosa2 · Andrea Urbani1,4 · Adalet Meral Gunes5 · Angelo Minucci1 Received: 15 June 2020 / Accepted: 9 September 2020 © Springer Nature B.V. 2020
Abstract Pyruvate kinase deficiency (PKD) is the most common glycolytic defect leading to chronic nonspherocytic hemolytic anemia (CNSHA). Clinical manifestations of PKD reflect the symptoms and complications of the chronic hemolysis, including anemia, jaundice, bilirubin gallstones due to hyperbilirubinemia, splenomegaly and iron overload. In this study, we report the finding of a 5-months-old Turkish male newborn with moderate CNSHA and PKD. Mutation screening of Pyruvate Kinase Liver/Red (PKLR) gene revealed that the patient carried the known pathogenic variant (PV) c.1456C > T (p.Arg486Trp) and an unreported variant c.1067T > G (p.Met356Arg). Computational variant analysis (CVA) highlighted the deleterious structural effects on the mutant PK enzyme, suggesting its pathogenic role. In this patient, the molecular evaluation of PKD, that allowed the identification of the novel PKLR genotype, coupled with CVA led to the definitive and correct diagnosis of CNSHA. Keywords Computational variant analysis · PK deficiency · Novel PKLR genotype Abbreviations PKD Pyruvate kinase deficiency CNSHA Chronic nonspherocytic hemolytic anemia PV Pathogenic variant CVA Computational variant analysis PKLR Pyruvate kinase liver red cells Giulia Canu and Elisa De Paolis equally contributed as first authors. * Andrea Urbani [email protected] * Angelo Minucci [email protected]; [email protected] 1
Molecular and Genomic Diagnostics Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
2
Istituto Di Chimica del Riconoscimento Molecolare (ICRM) – CNR; Institute of Chemical Sciences and Technologies “Giulio Natta” (SCITEC) - CNR, Rome, Italy
3
Università Federico II-CEINGE, Biotecnologie Avanzate, Naples, Italy
4
Catholic University of the Sacred Heart, Rome, Italy
5
Department of Pediatric Hematology, Uludağ University Hospital, Görükle, Bursa, Turkey
G2P2A1 Gestation 2 partum 2 alive 1 TB Total bilirubin UGT1A1 UDP-glucuronosyltransferase WT Wild type PDB Protein Data Bank
Introduction Pyruvate kinase deficiency (PKD) (OMIM 609712) is the most common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA) [1]. In CNSHA-PKD dependent, the complex and broad spectrum of clinical manifestations, ranging from a mildly symptomatic anemia to one that requires regular transfusions, can make final diagnosis difficult [2, 3]. Measurement of PK enzyme activity is a relatively fast and cheap method for PKD diagnosis. However, it may give false negative results, principally related to markedly increased reticulocytes,
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