Alu element insertion in PKLR PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients

Lesmana Harry; Dyer Lisa; Li Xia; Denton James; Griffiths Jenna; Chonat Satheesh; Seu Katie G.; Heeney Matthew M.; Zhang Kejian; Hopkin Robert J.; Kalfa Theodosia A.

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Alu element insertion in PKLR PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients

机译：alu元素插入pklr pklr基因作为中东患者丙酮酸激酶缺乏的新颖原因

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Abstract Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR ‐gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion‐dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD.

机译：摘要丙酮酸激酶缺乏（PKD）是糖酵解途径中最常见的红细胞酶异常以及遗传性无蜂科溶血性贫血的最常见原因。已经描述了超过250个PKLR-基突变，包括畸形/废话，剪接和调节突变，小插入，小和缺失，导致可变严重程度的PKD和溶血性贫血。 Alu Retrotransposons是人类基因组中最丰富的移动DNA序列，有助于其质量的近11％。通过破坏编码区域或接头信号，Alu插入与许多人类疾病有关。在这里，我们报告了两种无关的中东患者，既从血缘父母出生，均依赖于输血依赖性溶血性贫血，其中序列分析显示出PKLR基因的外显子6内aluyB9的纯合插入，导致PKLR RNA水平急性降低。该ALU元素插入包括先前未被识别的PKD发病机制的未被识别的机制。

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《Human mutation》 |2018年第3期|共5页
作者
Lesmana Harry; Dyer Lisa; Li Xia; Denton James; Griffiths Jenna; Chonat Satheesh; Seu Katie G.; Heeney Matthew M.; Zhang Kejian; Hopkin Robert J.; Kalfa Theodosia A.;
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作者单位

Division of Human GeneticsUniversity of Cincinnati College of MedicineCincinnati Ohio;

Division of Human GeneticsUniversity of Cincinnati College of MedicineCincinnati Ohio;

Division of Human GeneticsUniversity of Cincinnati College of MedicineCincinnati Ohio;

Division of Human GeneticsUniversity of Cincinnati College of MedicineCincinnati Ohio;

Division of Human GeneticsUniversity of Cincinnati College of MedicineCincinnati Ohio;

The Aflac Cancer and Blood Disorders CenterEmory University School of MedicineAtlanta Georgia;

Cancer and Blood Diseases InstituteUniversity of Cincinnati College of MedicineCincinnati Ohio;

Dana‐Farber/Boston Children's Cancer and Blood Disorders CenterHarvard Medical SchoolBoston;

Division of Human GeneticsUniversity of Cincinnati College of MedicineCincinnati Ohio;

Division of Human GeneticsUniversity of Cincinnati College of MedicineCincinnati Ohio;

Cancer and Blood Diseases InstituteUniversity of Cincinnati College of MedicineCincinnati Ohio;

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原文格式 PDF
正文语种 eng
中图分类医学遗传学;
关键词
AluYb9; hemolytic anemia; insertion mutation; PKLR; pyruvate kinase deficiency; retrotransposon; transposable element;

机译：aluyb9;溶血性贫血;插入突变;pklr;丙酮酸激酶缺乏;转回转换元件;

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专利

1. Alu element insertion in PKLR PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients [J] . Lesmana Harry, Dyer Lisa, Li Xia, Human mutation . 2018,第3期

机译：alu元素插入pklr pklr基因作为中东患者丙酮酸激酶缺乏的新颖原因
2. Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency. [J] . Indo Y, Mardy S, Miura Y, Human mutation . 2001,第4期

机译：先天性对无汗症疼痛（CIPA）不敏感：TRKA（NTRK1）基因的新突变，推定的单亲二体性，以及突变的TRKA和PKLR基因与CIPA和丙酮酸激酶缺乏症家庭的联系。
3. Gene editing of PKLR gene in hematopoietic cells for the efficient correction of pyruvate kinase deficiency [J] . Fananas-Baquero S., Quintana-Bustamante O., Alberquilla O., Human gene therapy . 2018,第12期

机译：造血细胞PKLR基因的基因编辑，以有效校正丙酮酸激酶缺乏
4. The Response of the Metabolic Network of the Red Blood Cell to Pyruvate Kinase Deficiency [C] . Xiaoliang Sun, Zuhong Lu . 2005

机译：红细胞代谢网络对丙酮酸激酶缺乏症的反应
5. Identification and characterization of hepatocyte-specific regulatory regions of the rat pyruvate kinase L gene : the synergistic effects of multiple elements. [D] . 山田, 一哉 1993

机译：大鼠丙酮酸激酶L基因肝细胞特异性调控区的鉴定和表征：多种元素的协同作用。
6. Alu-Element Insertion in PKLR Gene as a Novel Cause of Pyruvate Kinase Deficiency in Middle Eastern Patients [O] . Harry Lesmana, Lisa Dyer, Xia Li, -1

机译：PKLR基因中的铝元素插入是中东患者丙酮酸激酶缺乏的新原因
7. Disruption of a novel regulatory element in the erythroid-specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. [O] . van Wijk R, van Solinge WW, Nerlov C, 2003

机译：人PKLR基因的红系特异性启动子中新的调节元件的破坏导致严重的丙酮酸激酶缺乏症。

Alu element insertion in PKLR PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients

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