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Dis Model Mech. 2017 Aug 1;10(8):1005-1013. doi: 10.1242/dmm.029116. Epub 2017 Jun 9.

A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen.

Author information

1
Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia.
2
Porphyria Reference Laboratory, Biochemistry Department, Royal Melbourne Hospital, Parkville 3050, Australia.
3
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
4
Central Clinical School, Monash University, Melbourne 3004, Australia.
5
Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia david.curtis@monash.edu.

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.

KEYWORDS:

Anaemia; CPOX; Ethyl-N-nitrosourea; Hereditary coproporphyria

PMID:
28600349
PMCID:
PMC5560062
DOI:
10.1242/dmm.029116
[Indexed for MEDLINE]
Free PMC Article

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