Molecular characterization of six new cases of red blood cell hexokinase deficiency yields four novel mutations in HK1

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• 作者：Pavla Koralkova^a ; ^b ; Renata Mojzikova^a ; Brigitte van Oirschot^b ; Christine Macartney^c ; Pavel Timr^d ; Joan Lluis Vives Corrons^e ; Zuzana Striezencova Laluhova^f ; Katerina Lejhancova^g ; Vladimir Divoky^a ; ^h ; Richard van Wijk^b ; ^{r.vanwijk@umcutrecht.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Red blood cells ; Glycolysis ; Hexokinase deficiency ; Hemolytic anemia
• 刊名：Blood Cells, Molecules and Diseases
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：59
• 期：Complete
• 页码：71-76
• 全文大小：624 K

文摘

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.