A Family Affected by a Life-Threatening Erythrocyte Defect Caused by Pyruvate Kinase Deficiency With Normal Iron
Karolina Maciak1, Anna Adamowicz-Salach2, Jaroslaw Poznanski1
1Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Insights
Red cell pyruvate kinase deficiency (PKD) causes severe anemia. This study identified new mutations in a Polish family and found they lack iron overload due to a hepcidin-independent mechanism, despite frequent transfusions.
Area of Science:
- Genetics
- Hematology
- Biochemistry
Background:
- Red cell pyruvate kinase deficiency (PKD) is an inherited metabolic disorder affecting glycolysis, leading to congenital non-spherocytic hemolytic anemia.
- PKD presents with variable clinical severity, ranging from mild anemia to life-threatening conditions requiring lifelong transfusions and risking iron overload.
Purpose of the Study:
- To investigate the genetic basis of severe hemolytic anemia in a Polish family.
- To explore the mechanisms of iron regulation in transfusion-dependent patients with PKD.
Main Methods:
- Whole exome sequencing to identify genetic mutations.
- Molecular modeling to assess the impact of mutations on PKLR protein structure and function.
- Analysis of iron levels and hepcidin in patient serum.
Main Results:
- Identified two heterozygous mutations (c.1529 G > A and c.1495 T > C) in the PKLR gene in affected family members.
- Molecular modeling indicated significant disruption of PKLR protein structure and function.
- Patients were homozygous for TMPRSS6 variant rs855791 and showed undetectable hepcidin levels without signs of iron overload despite frequent transfusions.
Conclusions:
- The findings suggest a hepcidin-independent mechanism prevents iron overload in transfusion-dependent PKD patients.
- This highlights a novel aspect of iron regulation in the context of severe hemolytic anemia.
Background:
Red cell pyruvate kinase deficiency (PKD) is a defect of glycolysis causing congenital non-spherocytic hemolytic anemia. PKD is transmitted as an autosomal recessive trait. The clinical features of PKD are highly variable, from mild to life-threatening anemia which can lead to death in the neonatal period. Most patients with PKD must receive regular transfusions in early childhood and as a consequence suffer from iron overloading.
Patient:
Here, we report a Polish family with life-threatening hemolytic anemia of unknown etiology. Whole exome sequencing identified two heterozygous mutations, c.1529 G > A (p.R510Q) and c.1495 T > C (p.S499P) in the PKLR gene. Molecular modeling showed that the both PKLR mutations are responsible for major disturbance of the protein structure and functioning. Despite frequent transfusions the patients do not show any signs of iron overload and hepcidin, a major regulator of iron uptake, is undetectable in their serum. The patients were homozygous for the rs855791 variant of the TMPRSS6 gene which has earlier been shown to down-regulate iron absorption and accumulation.
Conclusion:
The lack of iron overload despite a reduced level of hepcidin in two transfusion-dependent PKD patients suggests the existence of a hepcidin-independent mechanism of iron regulation preventing iron overloading.
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