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Other entities represented in this entry:
SNOMEDCT: 111571009; ORPHA: 1195; DO: 0050649;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q22.1 | Atransferrinemia | 209300 | Autosomal recessive | 3 | TF | 190000 |
A number sign (#) is used with this entry because atransferrinemia is caused by homozygous or compound heterozygous mutation in the structural gene for transferrin (TF; 190000) on chromosome 3q22. Variation in the TF gene also affects serum transferrin levels.
A second transferrin serum level quantitative trait locus (TFQTL2; 614193) has been mapped to chromosome 6p22.
Atransferrinemia is characterized by microcytic anemia and by iron loading. It can be treated effectively by plasma infusions (summary by Beutler et al., 2000).
Heilmeyer et al. (1961) described total absence of transferrin in a 7-year-old girl whose presenting complaint was severe hypochromic anemia. Death occurred from heart failure. Severe hemosiderosis of the heart and liver was found at autopsy. About half-normal levels of transferrin in both parents supported recessive inheritance (Goya et al., 1972).
Goya et al. (1972) described a patient with only a trace of transferrin in the blood by immunologic methods, who responded well to parenteral administration of transferrin. Hayashi et al. (1993) restudied the family reported by Goya et al. (1972). The proband showed late onset of anemia and growth retardation (at age 7 years) and was found to have a healthy brother and a sister with very low transferrin levels. Supplementary therapy with apo-TF over a period of 5 years resulted in gradual disappearance of the anemia and improvement in growth. Severe deficiency of both TF and haptoglobin were demonstrated by immunoelectrophoretic studies. Recovery from anemia and the resumption of growth were dependent, however, only on his TF level. Hayashi et al. (1993) suggested that TF values less than 10 mg/dl may result in severe growth retardation and anemia, whereas persons with more than 20 mg/dl are apparently healthy. They also suggested that coexisting haptoglobin deficiency may alleviate hemosiderosis. Study by isoelectric focusing disclosed that there was a small amount of TF variant present in all 3 sibs, and that the variant was produced by an allelic gene derived from their father. For that reason, Hayashi et al. (1993) suggested that the condition be termed hypotransferrinemia, that it is a recessive trait, and that subjects with the recessive phenotype may be compound heterozygotes of a 'variant' allele and a 'null' allele.
Westerhausen and Meuret (1977) observed an acquired (autoimmune) form of atransferrinemia.
Serum Transferrin Quantitative Trait Locus
Benyamin et al. (2009) provided evidence that variation in the TF gene was associated with serum transferrin levels. A genomewide association study of 411 adolescent twins and their sibs, all of European descent, demonstrated that rs1830084, located 3-prime to the TF gene, was significantly associated with serum transferrin levels (p = 1.0 x 10(-9)). A second scan on an independent sample of 459 female monozygotic twin pairs found an association with rs3811647 within intron 11 of the TF gene (p = 3 x 10(-15)). The second scan also identified 2 additional and independent SNPs in TF (rs1799852 and rs2280673) that were associated with serum transferrin levels. The known C282Y variant in the HFE gene (613609.0001) was independently associated with serum transferrin (p = 1.1 x 10(-10)). The 3 TF SNPs found in the second scan plus the HFE C282Y mutation explained about 40% of genetic variation in serum transferrin levels (p = 7.8 x 10(-25)).
Beutler et al. (2000) stated that atransferrinemia had been reported in only 8 patients in 6 families. They reported the first known case in the United States and identified compound heterozygous mutations in the TF gene (190000.0006-190000.0007).
Craven et al. (1987) studied hypotransferrinemia in the mouse. The tissue distribution of iron overload was similar to that in hemochromatosis; the hypotransferrinemic mice accumulated iron in the liver and pancreas. The authors suggested that hereditary hemochromatosis (235200) and congenital atransferrinemia in man are one and the same disease and that they are associated with subnormal concentration of plasma apo-transferrin. Inasmuch as the transferrin locus maps to chromosome 3 and the hemochromatosis locus to chromosome 6, the suggestion that the atransferrinemic mouse is a model of hemochromatosis cannot be extended to the level of the gene.
Benyamin, B., McRae, A. F., Zhu, G., Gordon, S., Henders, A. K., Palotie, A., Peltonen, L., Martin, N. G., Montgomery, G. W., Whitfield, J. B., Visscher, P. M. Variants in TF and HFE explain about 40% of genetic variation in serum-transferrin levels. Am. J. Hum. Genet. 84: 60-65, 2009. [PubMed: 19084217] [Full Text: https://doi.org/10.1016/j.ajhg.2008.11.011]
Beutler, E., Gelbart, T., Lee, P., Trevino, R., Fernandez, M. A., Fairbanks, V. F. Molecular characterization of a case of atransferrinemia. Blood 96: 4071-4074, 2000. [PubMed: 11110675]
Craven, C. M., Alexander, J., Eldridge, M., Kushner, J. P., Bernstein, S., Kaplan, J. Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. Proc. Nat. Acad. Sci. 84: 3457-3461, 1987. [PubMed: 3472216] [Full Text: https://doi.org/10.1073/pnas.84.10.3457]
Goya, N., Miyazaki, S., Kodate, S., Ushio, B. A family of congenital atransferrinemia. Blood 40: 239-245, 1972. [PubMed: 4625559]
Hayashi, A., Wada, Y., Suzuki, T., Shimizu, A. Studies on familial hypotransferrinemia: unique clinical course and molecular pathology. Am. J. Hum. Genet. 53: 201-213, 1993. [PubMed: 8317485]
Heilmeyer, L., Keller, W., Vivell, O., Keiderling, W., Betke, K., Wohler, F., Schultze, H. E. Kongenitale Atransferrinaemie bei einem sieben Jahre alten Kind. Dtsch. Med. Wschr. 86: 1745-1751, 1961. [PubMed: 13906010] [Full Text: https://doi.org/10.1055/s-0028-1113001]
Heilmeyer, L., Merker, H., Wetzel, H. P., Burmeister, P., Haas, R. Atransferrinaemie bei nephrotischem Syndrom. Dtsch. Med. Wschr. 90: 1649-1656, 1965. [PubMed: 5829804] [Full Text: https://doi.org/10.1055/s-0028-1113395]
Heilmeyer, L. Die Atransferrinaemien. Acta Haemat. 36: 40-49, 1966. [PubMed: 4959651] [Full Text: https://doi.org/10.1159/000209090]
Westerhausen, M., Meuret, G. Transferrin-immune complex disease. Acta Haemat. 57: 96-101, 1977. [PubMed: 139071] [Full Text: https://doi.org/10.1159/000207865]