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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2607.
CORRESPONDENCE To the editor:Molecular characterization of a third case of human atransferrinemiaAtransferrinemia/hypotransferrinemia is an unusual disorder generally inherited in an autosomal recessive pattern.1,2 The hypochromic, microcytic anemia and hemochromatotic siderosis seen in atransferrinemia/hypotransferrinemia are of interest, as they provide clues to mechanisms and tissue distributions of iron-handling pathways that do not involve transferrin.1 A spontaneously arisen form of atransferrinemia in the mouse has been traced to a splice-site mutation in Tf,3 the orthologue of TF, which encodes transferrin in humans. The molecular-genetic basis of atransferrinemia/hypotransferrinemia has been previously determined in only 2 human instances. One proband, a woman, was found to be a compound heterozygote for mutations in TF. These were 1429G>C (A477P) and 562_571del 572_580dup, resulting in a stop codon 27 amino acids downstream).1 (Several different nomenclatures have been used to designate transferrin mutations and polymorphisms. We use the recommended nomenclature,4,5 in which the A of the upstream ATG is counted as nucleotide number 1 and the initiator methionine is amino acid number 1.) Another, a boy,6-8 was a compound heterozygote for 1180G>A (E394K) and an inferred null allele not traced to mutation in either coding region or intron-exon junctions of TF.8 The second instance of atransferrinemia identified, described in 1968 and now analyzed at the molecular level, occurred in a Slovak girl,9-12 at present 34 years old. She came to medical attention at age 2 months with severe hypochromic, microcytic anemia; her healthy parents denied consanguinity. Atransferrinemia was diagnosed using serum electrophoresis. Serum transferrin concentrations in her parents, a brother, and a grandfather were approximately half normal values.9,11 Periodic infusions of purified transferrin led to improved erythropoiesis, although complications ascribed to siderosis developed.10-12 Blood from the girl, her parents, and her healthy brothers was used to establish lymphoblastoid lines (National Institute of General Medical Sciences [NIGMS] Human Genetic Mutant Cell Repository, Coriell Institute for Medical Research, Camden, NJ; GM10911-14 and GM10929). All 17 exons of TF, with intron-exon junctions, were sequenced from cell-line genomic DNA extracted by standard techniques. Primers and sequencing conditions are given elsewhere.1 A missense mutation (229G>A) in exon 3 predicted to result in a nonconservative amino acid change (D77N) was found in homozygous form (229A/A) in the proband (GM10914). The mutation segregated with disease status in parents (both heterozygous [229G/A]) and brothers (one heterozygous, one [GM10911] wild-type [229G/G]). The mutation was not found in 48 chromosomes from other subjects. The known polymorphisms –84G>G, –2G>G, IVS4 + 110T>T, IVS4-60T>T, 739T>T (L247L), IVS8 + 61C>C, and IVS10-23C>C also were identified in the proband. The proband came from a town of 7000 inhabitants in a relatively isolated region of West Slovakia. Given homozygosity in the proband for the 229G>A (D77N) mutation and for all markers (data not shown), it may safely be presumed that parental consanguinity was present, albeit unknown, rather than that the mutation arose independently twice. These findings establish the molecular-genetic etiology of a clinically severe form of atransferrinemia. The previously reported female patient1 came to medical attention, for anemia, at the age of only 20 years. The previously reported boy6-8 was first evaluated at the age of only 7 years, for pallor of new onset. Substitution of a polar asparagine residue for a negatively charged aspartate residue in the region of the human transferrin molecule encoded by exon 3 of TF appears largely to have abrogated synthesis or secretion of functional transferrin in our patient, whose disease was severe in early infancy. Molecular characterization of other instances of atransferrinemia may permit further correlations between mutation and clinical manifestations. Acknowledgements
We thank Z.
Correspondence: A. S. Knisely, Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom; e-mail: alex.knisely{at}kcl.ac.uk; or Ernest Beutler, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037; e-mail: beutler{at}scripps.edu
Supported by National Institutes of Health grants DK53505-04 and RR00833 and the Stein Endowment Fund.
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| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
tofková, Prof J. 
áp, and Prof A. Hromec for assistance in contacts with the family. 
ného diet'at'a. Cesk Pediatr. 1968;23: 1020-1025.
