Molecular heterogeneity of pyruvate kinase deficiency

Abstract

Red cell pyruvate kinase (PK) deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an autosomal recessive trait, is caused by mutations in the PKLR gene and is characterized by molecular and clinical heterogeneity; anemia ranges from mild or fully compensated hemolysis to life-threatening forms necessitating neonatal exchange transfusions and/or subsequent regular transfusion support; complications include gallstones, pulmonary hypertension, extramedullary hematopoiesis and iron overload. Since identification of the first pathogenic variants responsible for PK deficiency in 1991, more than 300 different variants have been reported, and the study of molecular mechanisms and the existence of genotype-phenotype correlations have been investigated in-depth. In recent years, during which progress in genetic analysis, next-generation sequencing technologies and personalized medicine have opened up important landscapes for diagnosis and study of molecular mechanisms of congenital hemolytic anemias, genotyping has become a prerequisite for accessing new treatments and for evaluating disease state and progression. This review examines the extensive molecular heterogeneity of PK deficiency, focusing on the diagnostic impact of genotypes and new acquisitions on pathogenic non-canonical variants. The recent progress and the weakness in understanding the genotype-phenotype correlation, and its practical usefulness in light of new therapeutic opportunities for PK deficiency are also discussed.

A Proposed Concept for Defective Mitophagy Leading to Late Stage Ineffective Erythropoiesis in Pyruvate Kinase Deficiency

“…The disease is caused by compound heterozygous or homozygous loss of function mutations in the PKLR gene encoding for liver and red blood cell specific pyruvate kinase (PK-R; Canu et al, 2016 ; Grace et al, 2019a ). Over the last decades more than 300 different pathogenic variants have been reported ( Bianchi and Fermo, 2020 ). In the last step of glycolysis, PK converts phosphoenolpyruvate (PEP) into pyruvate, thereby generating ATP, the sole source of energy of the mature red blood cell.…”

“…Clinical features of PKD vary widely and range from mild anemia to red cell transfusion dependency. The relationship between genotype and phenotype is still incompletely understood ( Bianchi and Fermo, 2020 ; Bianchi et al, 2020 ). The presence of compound heterozygous pathogenic missense mutations may lead to the presence of several different combinations of PK tetramers each with its own kinetic, allosteric, and structural properties ( van Wijk et al, 2009 ).…”

“…The presence of compound heterozygous pathogenic missense mutations may lead to the presence of several different combinations of PK tetramers each with its own kinetic, allosteric, and structural properties ( van Wijk et al, 2009 ). Thereby, individual differences in metabolic or proteolytic activity, differences in splenic function, or variation in expression of (compensating) PK isoenzymes and the activity of other compensating pathways may contribute to the disease phenotype, as well as epigenetic factors and co-inheritance of other (red cell) diseases ( Bianchi and Fermo, 2020 ). Treatment for PKD is generally supportive including splenectomy, blood transfusion, and iron chelation as main therapies.…”

Non-spherocytic hemolytic anemia caused by erythrocyte pyruvate kinase defiiency: the analysis of genetic defects in pediatric patients, living in Russian Federation

“…В рассмотренной нами группе у 46,34% пациентов выявлены не описанные ранее как патогенные генетические варианты, что превышает порог в 25% новых мутаций в популяции, согласно опубликованным международным данным [11]. В экзонах 3 и 12 мутации обнаружены не были, однако, согласно международным данным, в этих областях также возможно наличие патогенных вариантов [12]. На сегодняшний день, учитывая гетерогенность обнаруженных мутаций и небольшую выборку пациентов, проследить взаимосвязь генотипа с наиболее характерными клиническими проявлениями, а также тяжестью течения заболевания не представляется возможным.…”

“…Описаны мутации во всех 12 экзонах (чаще всего встречаются экзоны 7, 8, 9 и 11), а также единичные мутации в промоторной области гена [12]. Большую часть мутаций составляют точечные миссенс-мутации, приводящие к функциональным и/или структурным нарушениям белка (66-70% от общего числа мутаций в зависимости от географического региона), и мутации сайта сплайсинга (13%) [11][12][13][14]. Для некоторых стран обнаружены более частые мутации гена PKLR: замена c.1529G>A (p.R510Q) у пациентов Северной и Центральной Европы и США; c.1456C>T (p.R486W) -в странах Южной и Западной Европы; с.…”