Pastore Yves, Jedlickova Katerina, Guan Yongli, Liu Enli, Fahner James, Hasle Henrik, Prchal Jaroslav F, Prchal Josef T
Texas Children's Cancer Center and Hematology Service and Baylor College of Medicine and Veterans Administration Hospital, Houston, TX, 77030, USA.
Am J Hum Genet. 2003 Aug;73(2):412-9. doi: 10.1086/377108. Epub 2003 Jul 3.
The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1 alpha (HIF-1 alpha) and serves as a recognition component of an E3-ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1 alpha forms a heterodimer with HIF-beta and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO). The autosomal dominant cancer-predisposition von Hippel-Lindau (VHL) syndrome is due to inheritance of a single mutated allele of VHL. In contrast, we recently showed that homozygous germline 598C-->T VHL mutation leads to Chuvash polycythemia (CP). We subsequently found VHL mutations in three unrelated individuals unaffected with CP, one of whom was compound heterozygous for the 598C-->T mutation and another VHL mutation. We now report seven additional polycythemic patients with VHL mutations in both alleles. Two Danish siblings and another American boy were homozygous for the VHL 598C-->T mutation. Three unrelated white Americans were compound heterozygotes for 598C-->T and another VHL mutation, 562C-->G in two and 574C-->T in the third. Additionally, a Croatian boy was homozygous for a 571C-->G VHL mutation, the first example of homozygous VHL germline mutation causing polycythemia, other than the VHL 598C-->T mutation. We have not observed VHL syndrome-associated tumors in polycythemic subjects or their heterozygous relatives; however, this will need to be evaluated by longitudinal studies. Over all, we found that up to half of the consecutive patients with apparent congenital polycythemia and increased serum Epo we have examined have mutations of both VHL alleles. Those findings, along with reports of CP, underscore that VHL mutations are the most frequent cause of congenital polycythemia and define a new class of polycythemic disorder, polycythemias due to augmented hypoxia sensing.
冯·希佩尔-林道（pVHL）蛋白在缺氧感知中起重要作用。它与羟基化的缺氧诱导因子1α（HIF-1α）结合，并作为E3泛素连接酶复合物的识别成分。在缺氧或继发于VHL基因突变时，未降解的HIF-1α与HIF-β形成异二聚体，导致缺氧诱导基因（包括促红细胞生成素（EPO））的转录增加。常染色体显性遗传性癌症易感性冯·希佩尔-林道（VHL）综合征是由于VHL的单个突变等位基因的遗传。相比之下，我们最近发现纯合子种系598C→T VHL突变导致楚瓦什红细胞增多症（CP）。我们随后在三名未患CP的无关个体中发现了VHL突变，其中一人为598C→T突变和另一个VHL突变的复合杂合子。我们现在报告另外7例两个等位基因均有VHL突变的红细胞增多症患者。两名丹麦兄弟姐妹和另一名美国男孩为VHL 598C→T突变的纯合子。三名无关的美国白人是598C→T与另一个VHL突变的复合杂合子，其中两人为562C→G突变，第三人为574C→T突变。此外，一名克罗地亚男孩为571C→G VHL突变的纯合子，这是除VHL 598C→T突变外，导致红细胞增多症的纯合子VHL种系突变的首个例子。我们在红细胞增多症患者或其杂合子亲属中未观察到VHL综合征相关肿瘤；然而，这需要通过纵向研究进行评估。总体而言，我们发现，在我们检查的明显先天性红细胞增多症且血清Epo升高的连续患者中，高达一半的患者有两个VHL等位基因的突变。这些发现，连同CP的报告，强调VHL突变是先天性红细胞增多症最常见的原因，并定义了一类新的红细胞增多症疾病，即由于缺氧感知增强导致的红细胞增多症。
