Sokol L, Luhovy M, Guan Y, Prchal J F, Semenza G L, Prchal J T
Division of Hematology/Oncology, University of Alabama at Birmingham 35294, USA.
Blood. 1995 Jul 1;86(1):15-22.
Primary familial and congenital polycythemia (PFCP) is characterized by erythrocytosis with normal arterial PO2, blood P50, and serum erythropoietin (EPO) levels. In two PFCP families EPO receptor (EPOR) polymorphisms cosegregated with PFCP. A heterozygous insertion of G at EPOR nucleotide 5975 was identified in genomic DNA from polycythemic members of family no. 2. 5974insG shifts the reading frame at codon 430, predicting amino acid substitutions and truncation of the last 64 amino acids. Wild-type and mutant EPOR transcripts were detected in erythroid progenitors from affected individuals. Burst-forming units-erythroid from patients exhibited increased colony size and sensitivity to EPO. Transfected Ba/F3 cells expressing EPOR 5974insG exhibited increased EPO sensitivity compared with cells expressing wild-type EPOR. The functional effect of this EPOR mutation was directly compared with the other C-terminal mutations reported in unrelated PFCP families by expression in Ba/F3 cells. The transfected cells with another primary polycythemia associated EPOR mutant construct (G6002A) also exhibited increased sensitivity to EPO.
原发性家族性和先天性红细胞增多症（PFCP）的特征是红细胞增多，动脉血氧分压、血液P50和血清促红细胞生成素（EPO）水平正常。在两个PFCP家族中，促红细胞生成素受体（EPOR）多态性与PFCP共分离。在2号家族红细胞增多症成员的基因组DNA中，发现EPOR核苷酸5975处有一个杂合的G插入。5974insG导致第430位密码子的阅读框移位，预测氨基酸替换并截短最后64个氨基酸。在受影响个体的红系祖细胞中检测到野生型和突变型EPOR转录本。患者的爆式红细胞集落形成单位表现出集落大小增加和对EPO的敏感性增加。与表达野生型EPOR的细胞相比，表达EPOR 5974insG的转染Ba/F3细胞表现出对EPO的敏感性增加。通过在Ba/F3细胞中表达，将这种EPOR突变的功能效应与无关PFCP家族中报道的其他C末端突变直接进行了比较。转染了另一种与原发性红细胞增多症相关的EPOR突变构建体（G6002A）的细胞也表现出对EPO的敏感性增加。
