Disturbance in the HIF-1α pathway associated with erythrocytosis:: Further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene
Disturbance in the HIF-1α pathway associated with erythrocytosis:: Further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene
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DOI：
10.1016/j.bcmd.2007.07.017
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发表时间：
2008-03-01
影响因子：
2.3
通讯作者：
Prehu, Claude
中科院分区：
文献类型：
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作者：
Al-Sheikh, Maha;Moradkhani, Kamran;Prehu, Claude
缺氧诱导因子HIF-1是细胞适应缺氧的关键调节因子。通过与VHL和激酶相互关联的复杂途径起作用，它调节大量基因，例如参与红细胞生成、糖酵解、pH调节和血管生成的基因。最近，脯氨酰羟化酶结构域蛋白2（PHD 2）基因中的错义突变[c.950C>G（p.Pro317Arg）]提供了PHD 2在家族性红细胞增多症病例中作用的证据，该基因编码的蛋白质具有HIF-1 α作为底物。在这项研究中，我们在74例不明红细胞增多症患者中寻找PHD 2基因突变。我们发现了两个移码突变的杂合子携带者[c.606de1G（p.Met202IlefsX71）和c.840- 841 insA（p.Arg281 ThrfsX 3）]。我都位于外显子1和杂合子携带者的无义突变[c。1129C>T（p.Gln377X）]。作为这些突变的结果，编码的PHD 2如果合成，将失去其催化活性。本文所述的遗传缺陷是PHD 2基因中报道的第一个移码和无义突变，并且与先前描述的错义突变一样，表明脯氨酰羟化酶活性降低干扰氧敏感途径可能是红细胞增多症的原因。除红细胞增多症外，在1例病例中观察到其他并发症，如炎性关节肌痛。(c)2007年爱思唯尔公司All rights reserved.
The hypoxia-inducible factor HIF-1 is the key regulator in cellular adaptation to hypoxia. Acting through a complex pathway, interconnected with VHL and kinases, it regulates a large number of genes, such as those involved in erythropoiesis, glycolysis, pH regulation, and angiogenesis. Recently, a missense mutation [c.950C>G (p.Pro317Arg)] in the prolyl hydroxylase domain protein 2 (PHD2) gene, whose encoded protein has HIF-1 alpha as a substrate, provided evidence of the PHD2 role in a case of familial erythrocytosis. In this study, we looked for mutations in the PHD2 gene, in 74 patients with unidentified erythrocytosis. We found two heterozygous carriers of frameshift mutations [c.606de1G (p.Met202IlefsX71) and c.840-841insA (p.Arg281 ThrfsX3)]. I both located in exon 1 and a heterozygous carrier of a nonsense mutation [c. 1129C>T (p. Gln377X)] in exon 3. As a result of these mutations the encoded PHD2, if synthesized, would lose its catalytic activity. The genetic defects herein described are the first frameshift and nonsense mutations reported in the PHD2 gene and, as the previous missense mutation described, suggest that a decreased prolyl hydroxylase activity disturbing the oxygen-sensing pathway might be the cause of erythrocytosis. In addition to erythrocytosis, other complications, such as inflammatory arthromyalgia, have been observed in one case. (c) 2007 Elsevier Inc. All rights reserved.