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 wildtype 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 hadnobiochemical 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1005-1013 |
| Number of pages | 9 |
| Journal | Disease Models and Mechanisms |
| Volume | 10 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 1 Aug 2017 |
Keywords
- Anaemia
- CPOX
- Ethyl-N-nitrosourea
- Hereditary coproporphyria
Cite this
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A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen. / Conway, Ashlee J.; Brown, Fiona C.; Fullinfaw, Robert O.; Kile, Benjamin T.; Jane, Stephen M.; Curtis, David J.
In: Disease Models and Mechanisms, Vol. 10, No. 8, 01.08.2017, p. 1005-1013.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen
AU - Conway, Ashlee J.
AU - Brown, Fiona C.
AU - Fullinfaw, Robert O.
AU - Kile, Benjamin T.
AU - Jane, Stephen M.
AU - Curtis, David J.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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 wildtype 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 hadnobiochemical 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.
AB - 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 wildtype 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 hadnobiochemical 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.
KW - Anaemia
KW - CPOX
KW - Ethyl-N-nitrosourea
KW - Hereditary coproporphyria
UR - http://www.scopus.com/inward/record.url?scp=85027397609&partnerID=8YFLogxK
U2 - 10.1242/dmm.029116
DO - 10.1242/dmm.029116
M3 - Article
VL - 10
SP - 1005
EP - 1013
JO - Disease Models and Mechanisms
JF - Disease Models and Mechanisms
SN - 1754-8403
IS - 8
ER -