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

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  • Ashlee J. Conway
    Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia
  • Fiona C. Brown
    Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia
  • Robert O. Fullinfaw
    Porphyria Reference Laboratory, Biochemistry Department, Royal Melbourne Hospital, Parkville 3050, Australia
  • Benjamin T. Kile
    ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
  • Stephen M. Jane
    Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia
  • David J. Curtis
    Australian Centre for Blood Diseases, Monash University and Clinical Haematology, Alfred Health, Melbourne 3004, Australia

Description

<jats:p>A genome-wide 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 cell phenotype in heterozygous mice. Urinary and faecal porphyrins in female RBC16 heterozygotes were significantly elevated compared to that of wildtype littermates, particularly coproporphyrinogen III, while 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.</jats:p>

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