Six novel variants in the PKLR gene associated with pyruvate kinase deficiency in Argentinian patients

Milanesio, Berenice; Pepe, Carolina; Defelipe, Lucas A.; Eberle, Silvia Eandi; Gómez, Vanesa Ávalos; Chaves, Alejandro; Albero, Agustina; Aguirre, Fernando; Fernández, Diego; Aizpurúa, Luciana; Dieuzeide, María Paula; Turjanski, Adrián; Bianchi, Paola; Fermo, Elisa; Feliú-Torres, Aurora

doi:10.1016/j.clinbiochem.2021.02.003

Cited by 7 publications

(4 citation statements)

References 20 publications

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“…The remaining 14 patients (74%) were compound heterozygous or homozygous for point variants in the PKLR gene (Table 1): 13 presented 2 missense variants (MS) and 1 had the combination of a missense with a null variant affecting splicing. Four of these variants (*) were novel and have been recently reported by members of our group [8]. Of the 27 alleles with MS variants, 7 (26%) carried the frequent variant in the Mediterranean population p.Arg486Trp [4].…”

Section: Resultsmentioning

confidence: 68%

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Multicenter Study of Pyruvate Kinase Deficiency in Argentina

et al. 2022

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The red blood cell (RBC) pyruvate kinase deficiency (PKD) is the most common recessive congenital defect of glycolytic enzymes associated with non-spherocytic hemolytic anemia. It is a rare hereditary disorder caused by >300 variants in the PKLR gene. This is a retrospective study of 19 patients from different centers from Argentina with confirmed molecular diagnosis of PKD. Clinical follow-up was carried out from birth in most cases. Five consanguineous patients from “gypsy” community, were homozygous for the “PK-Gypsy deletion” (PK-Gd). During the neonatal period they developed anemia with icterus. Transfusion exchange was required in 60%, light therapy in 80%, and RBC transfusion in 80%. During the follow-up iron overload was detected in the 100%, cholecystectomy was indicated in 40%, and splenectomy in 60%. Thirteen cases had 2 missense variants (MS), being the Mediterranean variant (p.Arg486Trp) the more frequent detected (26%).Only 1 patient had a missense-splicing mutation combination. During the neonatal period, 86% had anemia and icterus. Light therapy was required in 78%, transfusion exchange in 21% and RBC transfusion in 64%. During the follow-up iron overload was detected in 57% and splenectomy was indicated in 43%. Transfusions (pre-splenectomy and post-splenectomy) were more required in PK-Gd cases as compared with patients with point mutations (100%/60% vs 71%/29% respectively). Our data indicates a high clinical-therapeutic-molecular heterogeneity in PKD patients with the PK-Gd group presenting the most severe cases.

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Section: Resultsmentioning

confidence: 68%

“…Point variants and small deletions/insertions in the PKLR gene were analyzed by PCR-Sanger Sequencing [8] and the PK-GYPSY deletion was evaluated by GAP-PCR as previously described [9].…”

Section: Molecular Analysis Of the Pklr Genementioning

confidence: 99%

Multicenter Study of Pyruvate Kinase Deficiency in Argentina

et al. 2022

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“…It is highly conserved protein consisting of 4 subunits/domains: A, B, C, and Nter domain. The conformational space possesses mirror symmetric geometry [ 35 ]. In general, a highly elaborate functional unit is dependent upon the molecular structure of the protein.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate kinase deficiency and PKLR gene mutations: Insights from molecular dynamics simulation analysis

Wang,

Liu,

Liu

et al. 2024

Heliyon

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“…Clinical manifestations of PK deficiency are extremely variable, ranging from severe forms associated with intrauterine death, hydrops fetalis, or neonatal jaundice requiring exchange transfusions to fully compensated hemolytic anemia ( 4 ). Endocrinopathies, leg ulcers, bone disease, pulmonary hypertension, gallstones, and iron overload are common complications as well ( 5 ). Treatment options include chelation therapy, splenectomy, and red blood cell (RBC) transfusion.…”

Section: Introductionmentioning

confidence: 99%

Case report: Compound heterozygosity in PKLR gene with a large exon deletion and a novel rare p.Gly536Asp variant as a cause of severe pyruvate kinase deficiency

et al. 2022

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Red cell pyruvate kinase (PK) deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia and the most frequent enzyme abnormality of the glycolytic pathway. To the best of our knowledge, this is the first Korean PK deficiency study that analyzes copy number variation (CNV) using next-generation sequencing (NGS). A 7-year-old girl with jaundice was admitted for evaluation of a persistent hemolytic anemia. The proband appeared chronically ill, showing a yellowish skin color, icteric sclera, hepatomegaly, and splenomegaly on physical examination. Sequence variants and CNV generated from NGS data were estimated to determine if there was a potential genetic cause. As a result, compound heterozygosity in the PKLR gene for a large exon deletion between exon 3 and exon 9 accompanied with a novel rare p.Gly536Asp variant located on exon 10 was identified as a cause of severe PK deficiency in the proband. The PK activity of the proband had been measured at the time of day 1, 21, and 28 after receiving transfusion to indirectly assume the effect of the transfused blood, and the results were 100.9%, 73.0%, and 48.5%, compared with average of normal controls, respectively. Our report emphasizes the need to perform complete CNV analysis of NGS data and gene dosage assays such as multiplex ligation-dependent probe amplification to evaluate large deletions or duplications/insertions of the PKLR gene in patients with suspected PK deficiency.

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Six novel variants in the PKLR gene associated with pyruvate kinase deficiency in Argentinian patients

Cited by 7 publications

References 20 publications

Multicenter Study of Pyruvate Kinase Deficiency in Argentina

Multicenter Study of Pyruvate Kinase Deficiency in Argentina

Pyruvate kinase deficiency and PKLR gene mutations: Insights from molecular dynamics simulation analysis

Case report: Compound heterozygosity in PKLR gene with a large exon deletion and a novel rare p.Gly536Asp variant as a cause of severe pyruvate kinase deficiency

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