Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Am J Hematol. 2014 Apr;89(4):380-4. doi: 10.1002/ajh.23647. Epub 2014 Mar 3.
Red blood cell pyruvate kinase (PK-R) is a key regulatory enzyme of red cell metabolism. Hereditary deficiency of PK-R is caused by mutations in the PKLR gene, leading to chronic nonspherocytic hemolytic anemia. In contrast to PK deficiency, inherited PK hyperactivity has also been described. This very rare abnormality of RBC metabolism has been documented in only two families and appears to be without clinical consequences. Thus far, it has been attributed to either a gain of function mutation in PKLR or to persistent expression of the fetal PK isozyme PK-M2 in mature red blood cells. We here report on a novel type of inherited PK hyperactivity that is characterized by solely increased expression of a kinetically normal PK-R. In line with the latter, no mutations were detected in PKLR. Mutations in regulatory regions as well as variations in PKLR copy number were also absent. In addition, linkage analysis suggested that PK hyperactivity segregated independently from the PKLR locus. We therefore postulate that the causative mutation resides in a novel yet-unidentified locus, and upregulates PKLR gene expression. Other mutations of the same locus may be involved in those cases of PK deficiency that fail to reveal mutations in PKLR.
红细胞丙酮酸激酶（PK-R）是红细胞代谢的关键调节酶。PK-R 的遗传性缺乏是由 PKLR 基因突变引起的，导致慢性非球形红细胞溶血性贫血。与 PK 缺乏相反，也已经描述了遗传性 PK 活性过高。这种非常罕见的 RBC 代谢异常仅在两个家族中得到证实，似乎没有临床后果。到目前为止，它归因于 PKLR 中的功能获得性突变或成熟红细胞中胎儿 PK 同工酶 PK-M2 的持续表达。我们在这里报告一种新型的遗传性 PK 活性过高，其特征仅为动力学正常的 PK-R 表达增加。与后者一致，在 PKLR 中未检测到突变。调节区域的突变以及 PKLR 拷贝数的变化也不存在。此外，连锁分析表明 PK 活性过高与 PKLR 基因座独立分离。因此，我们推测致病突变位于一个尚未确定的新基因座，从而上调 PKLR 基因表达。同一基因座的其他突变可能与那些未能揭示 PKLR 突变的 PK 缺乏病例有关。
