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Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations
Serge Pissard1, Isabelle Max-Audit, Laurent Skopinski
1Laboratoire de Biochimie et de Génétique, AP-HP, Hôpital Henri-Mondor, Creteil, France. serge.pissard@im3.inserm.fr
Insights
Pyruvate kinase (PK) deficiency, the most common erythrocyte enzyme defect, is often underdiagnosed. This study identified 41 mutations, including 20 new ones, in families with PK deficiency, highlighting its potential severity and the need for prenatal diagnosis.
Area of Science:
- Biochemistry
- Genetics
- Hematology
Background:
- Pyruvate kinase (PK) deficiency is the most frequent enzyme defect in erythrocyte glycolysis.
- While often asymptomatic in heterozygotes, it causes severe conditions in homozygotes and compound heterozygotes.
- Over 180 mutations in the PK-LR gene are known, with more identified in this study.
Purpose of the Study:
- To detect mutations in pyruvate kinase (PK) deficiency associated with affected families.
- To characterize the molecular basis of PK deficiency in a cohort of families.
- To underscore the significance of PK deficiency, especially during the perinatal period.
Main Methods:
- Collected blood samples from 56 families with suspected PK deficiency.
- Measured haematological indices and erythrocyte enzyme activities (PK and glucose-6-phosphate dehydrogenase).
- Performed molecular characterization including restriction enzyme analysis, mutation scanning, and gene sequencing of the PK-LR gene.
Main Results:
- Identified nine homozygous cases and 41 distinct mutations among the studied families.
- Discovered 20 novel mutations affecting enzyme structure and seven new splice site mutations.
- Eight mutations affected splice sites, 31 were missense mutations in critical domains, and two were insertion-deletions.
Conclusions:
- Pyruvate kinase deficiency is an underdiagnosed condition with potentially life-threatening perinatal implications.
- The characterization of PK mutations aids in understanding disease mechanisms.
- Prenatal diagnosis is crucial for identifying affected infants and ensuring safer delivery outcomes.
Abstract:
Pyruvate kinase (PK) deficiency is the most common enzyme defect affecting the glycolytic pathway of the erythrocyte. Usually, it is clinically silent in heterozygotes but serious disorders are described at birth in homozygotes or compound heterozygotes. Including the mutants herein reported, more than 180 mutations of the PK-LR gene have now been identified. This 3-year study was carried out to detect mutations associated with disease-affecting families. Haematological indices, erythrocyte PK and glucose-6-phosphate dehydrogenase activities were measured. Molecular characterisation of the PK gene mutations included restriction enzyme analysis, mutation scanning and gene sequencing. Among the 56 families studied, nine homozygous cases and 41 different mutations were found. Eight mutations involved a splice site, 31 missense mutations were located in crucial domains of the molecule (catalytic site, cleft between the A and C domains, A/A' interface) and two cases of insertion-deletion were found. In total, 20 new mutations modifying the structure of the enzyme and seven affecting a splice site are reported. PK deficiency is an under diagnosed disease. However, deficiency could be life threatening in perinatal period and we report two lethal cases. These results support the characterisation of PK mutations, and show that prenatal diagnosis can identify affected infants and prepare safer conditions for the birth.
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