Alternative titles; symbols
ORPHA: 251380, 46532;
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38): X:9,600,001-17,400,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.2 | Fetal hemoglobin quantitative trait locus 3 | 305435 | X-linked | 2 |
For a general phenotypic description and a discussion of loci that may affect fetal hemoglobin production, see HBFQTL1 (141749).
Fetal hemoglobin (HbF) production varies over a 20-fold range and is under genetic control. Using microscopic radial immunodiffusion and flow cytometric immunofluorescent assays to determine the percentage of HbF-containing F reticulocytes and F cells in patients with sickle cell anemia (SS; 603903) and nonanemic persons, Dover et al. (1992) observed that the F-cell levels were significantly higher in nonanemic females than males (3.8% vs 2.7%) and that F-cell production as determined by F reticulocyte levels in SS females was also higher than in SS males (17% vs 13%).
Five factors have been hypothesized to influence the 20-fold variation in fetal hemoglobin levels in sickle-cell anemia: age, sex, alpha-globin gene number, beta-globin haplotype, and the X-linked F-cell production locus that regulates the production of HbF-containing erythrocytes (F cells). In studies of 112 SS patients living in France who were homozygous for the 3 common African beta-globin haplotypes (Benin, Bantu or Central African Republic, and Senegal), Chang et al. (1997) found that (1) FCP accounts for about 40% of the overall variation in HbF levels; (2) when the FCP influence is removed, beta-globin haplotype on chromosome 11p15 is associated with 14% of the remaining HbF variation; and (3) the other factors have little influence.
Miyoshi et al. (1986, 1988) suggested that high F-cell production is an X-linked trait on the basis of a frequency in females about twice that in males. Their attention was attracted to this possibility by studies of the Tokushima type of hereditary persistence of fetal hemoglobin. Miyoshi et al. (1988) found that among 300 healthy adults with various numbers of F cells, 2 different groups, a low and a high F-cell group, could be identified. Individuals with more than 4.4% of F cells (HbF about 0.7%) were defined as the high F-cell trait, which accounted for 11.3% of males and 20.7% of females. Family studies of 21 probands with this trait suggested X-linked dominant inheritance. Two families in which the trait was associated with colorblindness were described, although no definite evidence for linkage between the 2 could be obtained. Miyoshi et al. (1988) reviewed previously reported population and family studies and concluded that they also were consistent with X-linked dominant inheritance, including the family with so-called Swiss type of HPFH (Marti, 1963). Miyoshi et al. (1988) suggested that an X-linked gene controls gamma-globin gene expression by a trans-acting mechanism.
Chang et al. (1991) identified 15 sickle cell anemia families and 1 normal family in which transmission of F-cell levels was consistent with X linkage. They designed a single locus/2 allele model for assigning discrete F-cell phenotypes for linkage analysis. Testing of the model both by Hardy-Weinberg predictions and sib-pair analysis supported its validity. Linkage analysis yielded a maximum lod score of 4.22 at theta = 0.04 for RFLP markers at Xp22.2.
Dover et al. (1992) presented evidence supporting the hypothesis that F-cell production in both normal and anemic SS individuals is controlled by an X-linked locus with 2 alleles: high (H) and low (L). Using an algorithm to determine the 99.8% confidence interval of a normal distribution in nonanemic persons, they estimated that males and females with at least 1 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 2 phenotypes in SS males (L, less than 12%; H, greater than 12%) and 3 phenotypes in SS females (LL, less than 12%; HL, 12% to 24%; HH, greater than 24%). Linkage analysis using RFLPs situated on the X chromosome in 8 SS and 1 AA (normal hemoglobin) family localized the F-cell production (FCPX) locus to Xp22.2, with a maximum lod score of 4.6 at a recombination fraction of 0.04.
In a regression model, Chang et al. (1994) and Chang et al. (1995) found that the FCPX locus alone accounted for approximately 40% of the variation in Hb F level. When individuals with the high FCPX allele were removed from the analysis, the beta-globin haplotype contributed to more than 10% of the Hb F variation. Thus, the FCPX locus is the major determinant among known variables in Hb F production. Using 4 highly polymorphic dinucleotide repeat markers, Chang et al. (1994) and Chang et al. (1995) localized the FCPX locus to a 1-Mb minimal candidate region between DXS143 and DXS410.
Chang, Y.-P., Maier-Redelsperger, M., Smith, K. D., Contu, L., Ducrocq, R., de Mantalembert, M., Belloy, M., Eloin, J., Dover, G. J., Girot, R. The relative importance of the X-linked FCP locus and beta-globin haplotypes in determining haemoglobin F levels: a study of SS patients homozygous for beta(S) haplotypes. Brit. J. Haemat. 96: 806-814, 1997. [PubMed: 9074425] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.d01-2094.x]
Chang, Y. C., Dover, G. J., Meyers, D., Serjeant, G., Smith, K. D. Fetal hemoglobin level in adults is determined in part by a gene on the X-chromosome. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 16, 1991.
Chang, Y. C., Smith, K. D., Moore, R. D., Serjeant, G., Dover, G. J. The X-linked F cell production locus: genetic mapping and role in fetal hemoglobin production. (Abstract) Am. J. Hum. Genet. 55 (suppl.): A27, 1994.
Chang, Y. C., Smith, K. D., Moore, R. D., Serjeant, G. R., Dover, G. J. An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age. Blood 85: 1111-1117, 1995. [PubMed: 7531513]
Dover, G. J., Smith, K. D., Chang, Y. C., Purvis, S., Mays, A., Meyers, D. A., Sheils, C., Serjeant, G. Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2. Blood 80: 816-824, 1992. [PubMed: 1379090]
Marti, H. R. Normale und abnormale menschliche Haemoglobine. Berlin: Springer (pub.) 1963. P. 81.
Miyoshi, K., Kaneto, Y., Kawai, H., Ohchi, H., Niki, S., Hasegawa, K., Shirakami, A., Yamano, T. X-linked dominant control of F-cells in normal adult life: characterization of the Swiss type as hereditary persistence of fetal hemoglobin regulated dominantly by gene(s) on X chromosome. Blood 72: 1854-1860, 1988. [PubMed: 2461753]
Miyoshi, K., Keneto, Y., Kawai, H., Ohchi, H., Niki, S., Hasegawa, K., Adachi, K., Shirakami, A., Yamano, T. X-linked dominant control of F-cells in childhood and adult life. (Abstract) Jpn. J. Hum. Genet. 31: 202-203, 1986.