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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1113-1118
The molecular defect in hypotransferrinemic mice
Cameron C. Trenor III,
Dean R. Campagna,
Vera M. Sellers,
Nancy C. Andrews, and
Mark D. Fleming
From the Howard Hughes Medical Institute and Department of
Pathology, Children's Hospital and Harvard Medical School, Boston, MA.
Hypotransferrinemic (Trfhpx/hpx)
mice have a severe deficiency in serum transferrin (Trf) as the result
of a spontaneous mutation linked to the murine Trf locus. They
are born alive, but before weaning, die from severe anemia if they are
not treated with exogenous Trf or red blood cell transfusions. We have
determined the molecular basis of the hpx mutation. It results
from a single point mutation, which alters an invariable nucleotide in
the splice donor site after exon 16 of the Trf gene. No normal
Trf messenger RNA (mRNA) is made from the hpx allele. A
small amount of mRNA results from the usage of cryptic splice sites
within exon 16. The predominant cryptic splice site produces a
Trf mRNA carrying a 27-base pair (bp), in-frame deletion. Less
than 1% of normal levels of a Trf-like protein is found in the serum
of Trfhpx/hpx mice, most likely
resulting from translation of the internally deleted mRNA. Despite
their severe Trf deficiency, however,
Trfhpx/hpx mice initially
treated with transferrin injections can survive after weaning without
any further treatment. They have massive tissue iron overload develop
in all nonhematopoietic tissues, while they continue to have severe
iron deficiency anemia. Their liver iron burden is 100-fold greater
than that of wild-type mice and 15- to 20-fold more than that of mice
lacking the hemochromatosis gene, Hfe.
Trfhpx/hpx mice thus provide an
additional model with a defined molecular defect for
the study of genetic iron disorders.
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