Molecular characterization of six new cases of red blood cell hexokinase deficiency yields four novel mutations in HK1.
Hexokinase (HK) is a key enzyme of glycolysis, the only metabolic pathway able to provide the red blood cell with ATP. HK deficiency is a very rare hereditary disorder with severe chronic nonspherocytic hemolytic anemia (HNSHA) as a major clinical feature. To date, only 24 patients with HK deficiency have been identified. Here, we report the molecular analysis of six new cases of HK deficiency. A total of six different mutations were detected in HK1, four of them described here for the first time: c.2599C>T p.(His867Tyr), c.1799C>T p.(Thr600Met), c.873-2A>G and c.493-1G>A. The pathogenic nature of the identified missense mutations was confirmed by biochemical and 3-dimensional structural analysis. The effects of the novel splice site mutation c.873-2A>G were studied at the level of pre-mRNA processing, and confirmed at the protein level. All together, these results provide a better insight into the pathogenesis of this rare red cell disorder, and contribute to a better understanding of the genotype-phenotype correlation in HK deficiency.
Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic; Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Pavla
P
Koralkova
Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic.
Renata
R
Mojzikova
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Brigitte
B
van Oirschot
Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland, United Kingdom.
Christine
C
Macartney
Department of Pediatrics, Ceske Budejovice Hospital, Ceske Budejovice, Czech Republic.
Pavel
P
Timr
Hospital Clinic I Provencial, Barcelona, Spain.
Joan Lluis
JL
Vives Corrons
Children's Faculty Hospital with Policlinic, Bratislava, Slovak Republic.
Zuzana
Z
Striezencova Laluhova
Department of Paediatrics, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
Katerina
K
Lejhancova
Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic; Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry Palacký University, Olomouc, Czech Republic.
Vladimir
V
Divoky
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: r.vanwijk@umcutrecht.nl.
Richard
R
van Wijk
D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D056726:Genetic Association Studies; D006593:Hexokinase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics; D055815:Young Adult
D022821:RNA Splice Sites; C472074:HK1 protein, human; D006593:Hexokinase
Glycolysis; Hemolytic anemia; Hexokinase deficiency; Red blood cells