PYRUVATE KINASE DEFICIENCY

丙酮酸激酶缺乏症

• 批准号: 7391954
• 负责人: URS GIGER
• 金额: $ 0.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391954
• 关键词: PYRUVATE; KINASE; DEFICIENCY

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Erythrocyte pyruvate kinase (PK) deficiency is the most common glycolytic erythroenzymopathy in humans and resulats in a moderate to severe hemolytic anemia. Similarly, dogs with PK deficiency have severe hemolytic anemia, but they also develop a myelofibrosis and osteosclerosis. After the original discovery of the first mutation in PK-deficient beagles we have now identified disease causing mutations in West Highland white and Cairn terriers, Beagles, Eskimo toy, and dachshund. We also identified PK-deficiency in Abyssinian, Somali, and domestic shorthaired cats. These cats experienced an intermittent hemolytic anemia. Their erythrocytes have less than 10% PK activity and there is no anomalous expression of M-PK. Molecular genetic analysis revealed a 13bp deletion in exon 6 due to a single base pair mutation in intron 6 that results in alternate splicing and truncation of the protein. A small number of cats are being kept for collaborative gene transfer studies with Clint Lothrop, DVM, PhD at Auburn University. Despite the identification of the various mutations the full-length cDNA has not been reported. This is of particular interest as there is different splicing responsible for the R and L isoforms and the further structure may explain the anomalous expression of M-type PK in dogs, which seems to be dysfunctional in red blood cells. Based upon the recent completion of the canine genome sequence and partial information on the feline genome sequence, we should be able to complete these studies which will also permit the generation of species-specific full length cDNAs for gene transfer studies.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。红细胞丙酮酸激酶(PK)缺乏症是人类最常见的糖酵解性红细胞性酶病，可导致中度至重度溶血性贫血。同样，PK缺乏的狗有严重的溶血性贫血，但它们也会发展成骨髓纤维化和骨硬化症。在最初在PK缺陷的比格犬中发现第一个突变后，我们现在已经在西高地白梗和凯恩梗、比格犬、爱斯基摩玩具犬和腊肠犬中发现了导致疾病的突变。我们还在阿比西尼亚猫、索马里猫和家养短毛猫中发现了PK缺乏。这些猫经历了间歇性溶血性贫血。红细胞PK活性低于10%，未见M-PK异常表达。分子遗传学分析显示，由于内含子6的单个碱基对突变导致蛋白质的交替剪接和截断，导致外显子6有13bp的缺失。一小部分猫正在被饲养，用于与奥本大学的克林特·洛思罗普博士合作进行基因转移研究。尽管鉴定出了各种突变，但全长cDNAs尚未见报道。这一点特别令人感兴趣，因为R和L亚型存在不同的剪接，进一步的结构可能解释了狗M型PK的异常表达，这似乎是红细胞中的功能障碍。基于最近完成的犬类基因组序列和猫科动物基因组序列的部分信息，我们应该能够完成这些研究，这也将允许产生用于基因转移研究的特定物种的全长cDNA。