Dover G J, Smith K D, Chang Y C, Purvis S, Mays A, Meyers D A, Sheils C, Serjeant G
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Blood. 1992 Aug 1;80(3):816-24.
Fetal hemoglobin (Hb F) production in sickle cell (SS) disease and in normal individuals varies over a 20-fold range and is under genetic control. Previous studies suggested that variant Hb F levels might be controlled by genetic loci separate from the beta-globin complex on chromosome 11. Using microscopic radial immunodiffusion and flow cytometric immunofluorescent assays to determine the percentage of F reticulocytes and F cells in SS and nonanemic individuals, we observed that F-cell levels were significantly higher in nonanemic females than males (mean +/- SD, 3.8% +/- 3.2% v 2.7% +/- 2.3%). F-cell production as determined by F reticulocyte levels in SS females was also higher than in SS males (17% +/- 10% v 13% +/- 8%). We tested the hypothesis that F-cell production in both normal and anemic SS individuals was controlled by an X-linked locus with two alleles, high (H) and low (L). Using an algorithm to determine the 99.8% confidence interval of a normal distribution in nonanemic individuals, we estimated that males and females with at least one H allele had greater than 3.3% F cells. Comparisons of male-male or female-female SS sib pairs with discordant F reticulocyte levels distinguished two phenotypes in SS males (L, less than 12%; H, greater than 12%) and three phenotypes in SS females (LL, less than 12%; HL, 12% to 24%, HH greater than 24%). Linkage analysis using polymorphic restriction sites along the X chromosome in eight SS and one AA family localized the F-cell production (FCP) locus to Xp22.2, with a maximum lod score (logarithm of odds of linkage v independent assortment) of 4.6 at a recombination fraction of 0.04.
镰状细胞（SS）病患者和正常个体的胎儿血红蛋白（Hb F）产量相差20倍，且受基因控制。先前的研究表明，不同的Hb F水平可能由11号染色体上与β-珠蛋白复合体分开的基因位点控制。我们使用显微镜放射免疫扩散和流式细胞术免疫荧光测定法来确定SS患者和非贫血个体中F网织红细胞和F细胞的百分比，发现非贫血女性的F细胞水平显著高于男性（均值±标准差，3.8%±3.2%对2.7%±2.3%）。通过SS女性的F网织红细胞水平确定的F细胞生成量也高于SS男性（17%±10%对13%±8%）。我们检验了这样一个假设，即正常和贫血的SS个体中的F细胞生成均由一个X连锁基因位点控制，该位点有两个等位基因，即高（H）和低（L）。使用一种算法来确定非贫血个体中正态分布的99.8%置信区间，我们估计至少有一个H等位基因的男性和女性的F细胞大于3.3%。对F网织红细胞水平不一致的男性-男性或女性-女性SS同胞对进行比较，在SS男性中区分出两种表型（L，小于12%；H大于12%），在SS女性中区分出三种表型（LL，小于12%；HL，12%至24%，HH大于24%）。利用八个SS家族和一个AA家族中沿X染色体的多态性限制性位点进行连锁分析，将F细胞生成（FCP）基因位点定位到Xp22.2，在重组率为0.04时，最大连锁对数（连锁与独立分配的对数比）为4.6。
