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
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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