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RESEARCH ARTICLE
A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen
Ashlee J. Conway, Fiona C. Brown, Robert O. Fullinfaw, Benjamin T. Kile, Stephen M. Jane, David J. Curtis
Disease Models & Mechanisms 2017 10: 1005-1013; doi: 10.1242/dmm.029116
Ashlee J. Conway
1Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia
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Fiona C. Brown
1Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia
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Robert O. Fullinfaw
2Porphyria Reference Laboratory, Biochemistry Department, Royal Melbourne Hospital, Parkville 3050, Australia
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Benjamin T. Kile
3ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
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  • ORCID record for Benjamin T. Kile
Stephen M. Jane
1Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia
4Central Clinical School, Monash University, Melbourne 3004, Australia
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David J. Curtis
1Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia
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  • For correspondence: david.curtis@monash.edu
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ABSTRACT

A genome-wide ethyl-N-nitrosourea (ENU) mutagenesis screen in mice was performed to identify novel regulators of erythropoiesis. Here, we describe a mouse line, RBC16, which harbours a dominantly inherited mutation in the Cpox gene, responsible for production of the haem biosynthesis enzyme, coproporphyrinogen III oxidase (CPOX). A premature stop codon in place of a tryptophan at amino acid 373 results in reduced mRNA expression and diminished protein levels, yielding a microcytic red blood cell phenotype in heterozygous mice. Urinary and faecal porphyrins in female RBC16 heterozygotes were significantly elevated compared with that of wild-type littermates, particularly coproporphyrinogen III, whereas males were biochemically normal. Attempts to induce acute porphyric crises were made using fasting and phenobarbital treatment on females. While fasting had no biochemical effect on RBC16 mice, phenobarbital caused significant elevation of faecal coproporphyrinogen III in heterozygous mice. This is the first known investigation of a mutagenesis mouse model with genetic and biochemical parallels to hereditary coproporphyria.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Conceptualization: A.J.C., F.C.B., B.T.K., S.M.J., D.J.C.; Methodology: A.J.C., F.C.B., R.O.F., B.T.K.; Validation: A.J.C., F.C.B., S.M.J., D.J.C.; Formal analysis: A.J.C., D.J.C.; Investigation: A.J.C., F.C.B., R.O.F., B.T.K., D.J.C.; Resources: R.O.F., B.T.K., S.M.J., D.J.C.; Data curation: A.J.C., D.J.C.; Writing - original draft: A.J.C.; Writing - review & editing: F.C.B., B.T.K., S.M.J., D.J.C.; Visualization: B.T.K., S.M.J., D.J.C.; Supervision: F.C.B., S.M.J., D.J.C.; Project administration: B.T.K., S.M.J., D.J.C.; Funding acquisition: S.M.J., D.J.C.

  • Funding

    This work was supported in part by a Project Grant (382900) from the Australian National Health and Medical Research Council (NHMRC) awarded to S.M.J. and D.J.C. and a Viertel Senior Medical Research Fellowship awarded to D.J.C.

  • Received December 25, 2016.
  • Accepted June 2, 2017.
  • © 2017. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/3.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Ethyl-N-Nitrosourea
  • Hereditary coproporphyria
  • CPOX
  • Anaemia

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RESEARCH ARTICLE
A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen
Ashlee J. Conway, Fiona C. Brown, Robert O. Fullinfaw, Benjamin T. Kile, Stephen M. Jane, David J. Curtis
Disease Models & Mechanisms 2017 10: 1005-1013; doi: 10.1242/dmm.029116
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RESEARCH ARTICLE
A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen
Ashlee J. Conway, Fiona C. Brown, Robert O. Fullinfaw, Benjamin T. Kile, Stephen M. Jane, David J. Curtis
Disease Models & Mechanisms 2017 10: 1005-1013; doi: 10.1242/dmm.029116

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