Characterization of Tfrc-mutant mice with microcytic phenotypes

Research output: Contribution to journalArticleResearchpeer-review

Abstract

To identify novel regulators of erythropoiesis, we performed independent forward genetic screens using the chemical mutagen ENU in mice. Among progeny displaying microcytic red-cell phenotypes, 7 independent mouse strains harboring mutations within the transferrin receptor gene Tfrc were identified. Six of the mutants, including the previously described red blood cell 6 (RBC6) strain, displayed reduced erythroblast CD71 expression and midgestation lethality of homozygotes (E12.5-E14.5), and 1 novel strain, RBC21, displayed a variable phenotype with sustained CD71 expression and late homozygous lethality (E18.5). Standard iron studies were normal in the RBC21 mutant, but intracellular ferritin was significantly reduced. The microcytic phenotype seen in the RBC21 strain was the result of impaired binding of transferrin to the receptor. Neither RBC6 nor RBC21 responded to iron replacement therapy. These studies describe how point mutations of the transferrin receptor can cause a microcytic anemia that does not respond to iron therapy and would not be detected by routine iron studies, such as serum ferritin.
Original languageEnglish
Pages (from-to)1914-1922
Number of pages9
JournalBlood Advances
Volume2
Issue number5
DOIs
Publication statusPublished - 14 Aug 2018

Cite this

@article{3726331d763647ed95d027c499f49ae5,
title = "Characterization of Tfrc-mutant mice with microcytic phenotypes",
abstract = "To identify novel regulators of erythropoiesis, we performed independent forward genetic screens using the chemical mutagen ENU in mice. Among progeny displaying microcytic red-cell phenotypes, 7 independent mouse strains harboring mutations within the transferrin receptor gene Tfrc were identified. Six of the mutants, including the previously described red blood cell 6 (RBC6) strain, displayed reduced erythroblast CD71 expression and midgestation lethality of homozygotes (E12.5-E14.5), and 1 novel strain, RBC21, displayed a variable phenotype with sustained CD71 expression and late homozygous lethality (E18.5). Standard iron studies were normal in the RBC21 mutant, but intracellular ferritin was significantly reduced. The microcytic phenotype seen in the RBC21 strain was the result of impaired binding of transferrin to the receptor. Neither RBC6 nor RBC21 responded to iron replacement therapy. These studies describe how point mutations of the transferrin receptor can cause a microcytic anemia that does not respond to iron therapy and would not be detected by routine iron studies, such as serum ferritin.",
author = "Conway, {Ashlee Jade} and Brown, {Fiona C.} and Gerhard Rank and Kile, {Benjamin T.} and Morton, {Craig J.} and Jane, {Stephen M.} and Curtis, {David J.}",
year = "2018",
month = "8",
day = "14",
doi = "10.1182/bloodadvances.2018018820",
language = "English",
volume = "2",
pages = "1914--1922",
journal = "Blood Advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "5",

}

Characterization of Tfrc-mutant mice with microcytic phenotypes. / Conway, Ashlee Jade; Brown, Fiona C.; Rank, Gerhard; Kile, Benjamin T.; Morton, Craig J.; Jane, Stephen M.; Curtis, David J.

In: Blood Advances, Vol. 2, No. 5, 14.08.2018, p. 1914-1922.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Characterization of Tfrc-mutant mice with microcytic phenotypes

AU - Conway, Ashlee Jade

AU - Brown, Fiona C.

AU - Rank, Gerhard

AU - Kile, Benjamin T.

AU - Morton, Craig J.

AU - Jane, Stephen M.

AU - Curtis, David J.

PY - 2018/8/14

Y1 - 2018/8/14

N2 - To identify novel regulators of erythropoiesis, we performed independent forward genetic screens using the chemical mutagen ENU in mice. Among progeny displaying microcytic red-cell phenotypes, 7 independent mouse strains harboring mutations within the transferrin receptor gene Tfrc were identified. Six of the mutants, including the previously described red blood cell 6 (RBC6) strain, displayed reduced erythroblast CD71 expression and midgestation lethality of homozygotes (E12.5-E14.5), and 1 novel strain, RBC21, displayed a variable phenotype with sustained CD71 expression and late homozygous lethality (E18.5). Standard iron studies were normal in the RBC21 mutant, but intracellular ferritin was significantly reduced. The microcytic phenotype seen in the RBC21 strain was the result of impaired binding of transferrin to the receptor. Neither RBC6 nor RBC21 responded to iron replacement therapy. These studies describe how point mutations of the transferrin receptor can cause a microcytic anemia that does not respond to iron therapy and would not be detected by routine iron studies, such as serum ferritin.

AB - To identify novel regulators of erythropoiesis, we performed independent forward genetic screens using the chemical mutagen ENU in mice. Among progeny displaying microcytic red-cell phenotypes, 7 independent mouse strains harboring mutations within the transferrin receptor gene Tfrc were identified. Six of the mutants, including the previously described red blood cell 6 (RBC6) strain, displayed reduced erythroblast CD71 expression and midgestation lethality of homozygotes (E12.5-E14.5), and 1 novel strain, RBC21, displayed a variable phenotype with sustained CD71 expression and late homozygous lethality (E18.5). Standard iron studies were normal in the RBC21 mutant, but intracellular ferritin was significantly reduced. The microcytic phenotype seen in the RBC21 strain was the result of impaired binding of transferrin to the receptor. Neither RBC6 nor RBC21 responded to iron replacement therapy. These studies describe how point mutations of the transferrin receptor can cause a microcytic anemia that does not respond to iron therapy and would not be detected by routine iron studies, such as serum ferritin.

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DO - 10.1182/bloodadvances.2018018820

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