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A zebrafish model for hepatoerythropoietic porphyria

Abstract

Defects in the enzymes involved in the haem biosynthetic pathway can lead to a group of human diseases known as the porphyrias. yquem (yqetp61) is a zebrafish mutant with a photosensitive porphyria syndrome. Here we show that the porphyric phenotype is due to an inherited homozygous mutation in the gene encoding uroporphyrinogen decarboxylase (UROD); a homozygous deficiency of this enzyme causes hepatoerythropoietic porphyria (HEP) in humans. The zebrafish mutant represents the first genetically 'accurate' animal model of HEP, and should be useful for studying the pathogenesis of UROD deficiency and evaluating gene therapy vectors. We rescued the mutant phenotype by transient and germline expression of the wild-type allele.

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Figure 1: Zebrafish yqetp61 phenotype and UROD expression.
Figure 2: Porphyrin and UROD assays.
Figure 3: Alignment of UROD amino acid sequences from zebrafish, human, mouse, yeast and E.coli (ref 4-9)
Figure 4: Identification of a missense point mutation and linkage analysis.
Figure 5: Rescue effect in transient urod-GFP transgenic zebrafish.
Figure 6: Rescue effect in germline urod-GFP transgenic zebrafish.

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Acknowledgements

We thank B. Ong, B. Moore, H. Tang, N. Miller, C. Leithner and L. Garbaczewski for technical assistance; C. Nusslein-Volhard for providing fish blood mutants before publication; H. Dailey for assistance with preliminary enzyme assays and helpful suggestions; and R.-B. Markowitz, L. Zon, J. Postlethwait, Y. Yan, B. Paw and members of our laboratory for discussions. This work is supported in part by grants to S.L. from the American Heart Association Georgia Affiliate and NIH (RO1 DK54508-01), and to S.S. from USPHS (DK-32890). S.L. is a recipient of the American Society of Hematology Scholar Award.

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Correspondence to Shuo Lin.

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Wang, H., Long, Q., Marty, S. et al. A zebrafish model for hepatoerythropoietic porphyria. Nat Genet 20, 239–243 (1998). https://doi.org/10.1038/3041

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