montalcino, A zebrafish model for variegate porphyria

Kimberly A. Dooley, Paula G. Fraenkel, Nathaniel B. Langer, Bettina Schmid, Alan J. Davidson, Gerhard Weber, Ken Chiang, Helen Foott, Caitlin Dwyer, Rebecca A. Wingert, Yi Zhou, Barry H. Paw, Leonard I. Zon, F. Bebber van, E. Busch-Nentwich, R. Dahm, H. G. Frohnhöfer, H. Geiger, D. Gilmour, S. Holley & 30 others J. Hooge, D. Jülich, H. Knaut, F. Maderspacher, C. Neumann, Teresa Nicolson, C. Nüsslein-Volhard, H. Roehl, U. Schönberger, C. Seiler, C. Söllner, M. Sonawane, A. Wehner, C. Weiler, B. Schmid, U. Hagner, E. Hennen, C. Kaps, A. Kirchner, T. I. Koblizek, U. Langheinrich, C. Metzger, R. Nordin, M. Pezzuti, K. Schlombs, J. deSantana-Stamm, T. Trowe, G, Vacun, A. Walker, C. Weiler

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Objective: Inherited or acquired mutations in the heme biosynthetic pathway leads to a debilitating class of diseases collectively known as porphyrias, with symptoms that can include anemia, cutaneous photosensitivity, and neurovisceral dysfunction. In a genetic screen for hematopoietic mutants, we isolated a zebrafish mutant, montalcino (mno), which displays hypochromic anemia and porphyria. The objective of this study was to identify the defective gene and characterize the phenotype of the zebrafish mutant. Materials and Methods: Genetic linkage analysis was utilized to identify the region harboring the mno mutation. Candidate gene analysis together with reverse transcriptase polymerase chain reaction was utilized to identify the genetic mutation, which was confirmed via allele-specific oligo hybridizations. Whole mount in situ hybridizations and o-dianisidine staining were used to characterize the phenotype of the mno mutant. mRNA and morpholino microinjections were performed to phenocopy and/or rescue the mutant phenotype. Results: Homozygous mno mutant embryos have a defect in the protoporphyrinogen oxidase (ppox) gene, which encodes the enzyme that catalyzes the oxidation of protoporphyrinogen. Homozygous mutant embryos are deficient in hemoglobin, and by 36 hours post-fertilization are visibly anemic and porphyric. The hypochromic anemia of mno embryos was partially rescued by human ppox, providing evidence for the conservation of function between human and zebrafish ppox. Conclusion: In humans, mutations in ppox result in variegate porphyria. At present, effective treatment for acute attacks requires the administration intravenous hemin and/or glucose. Thus, mno represents a powerful model for investigation, and a tool for future screens aimed at identifying chemical modifiers of variegate porphyria.

Original languageEnglish (US)
Pages (from-to)1132-1142
Number of pages11
JournalExperimental Hematology
Volume36
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

Fingerprint

Variegate Porphyria
Zebrafish
Protoporphyrinogen Oxidase
Hypochromic Anemia
Porphyrias
Mutation
Embryonic Structures
Phenotype
Dianisidine
Morpholinos
Hemin
Genetic Linkage
Biosynthetic Pathways
Microinjections
Genetic Association Studies
Reverse Transcriptase Polymerase Chain Reaction
Heme
Fertilization
Intravenous Administration
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Dooley, K. A., Fraenkel, P. G., Langer, N. B., Schmid, B., Davidson, A. J., Weber, G., ... Weiler, C. (2008). montalcino, A zebrafish model for variegate porphyria. Experimental Hematology, 36(9), 1132-1142. https://doi.org/10.1016/j.exphem.2008.04.008

montalcino, A zebrafish model for variegate porphyria. / Dooley, Kimberly A.; Fraenkel, Paula G.; Langer, Nathaniel B.; Schmid, Bettina; Davidson, Alan J.; Weber, Gerhard; Chiang, Ken; Foott, Helen; Dwyer, Caitlin; Wingert, Rebecca A.; Zhou, Yi; Paw, Barry H.; Zon, Leonard I.; Bebber van, F.; Busch-Nentwich, E.; Dahm, R.; Frohnhöfer, H. G.; Geiger, H.; Gilmour, D.; Holley, S.; Hooge, J.; Jülich, D.; Knaut, H.; Maderspacher, F.; Neumann, C.; Nicolson, Teresa; Nüsslein-Volhard, C.; Roehl, H.; Schönberger, U.; Seiler, C.; Söllner, C.; Sonawane, M.; Wehner, A.; Weiler, C.; Schmid, B.; Hagner, U.; Hennen, E.; Kaps, C.; Kirchner, A.; Koblizek, T. I.; Langheinrich, U.; Metzger, C.; Nordin, R.; Pezzuti, M.; Schlombs, K.; deSantana-Stamm, J.; Trowe, T.; Vacun, G,; Walker, A.; Weiler, C.

In: Experimental Hematology, Vol. 36, No. 9, 09.2008, p. 1132-1142.

Research output: Contribution to journalArticle

Dooley, KA, Fraenkel, PG, Langer, NB, Schmid, B, Davidson, AJ, Weber, G, Chiang, K, Foott, H, Dwyer, C, Wingert, RA, Zhou, Y, Paw, BH, Zon, LI, Bebber van, F, Busch-Nentwich, E, Dahm, R, Frohnhöfer, HG, Geiger, H, Gilmour, D, Holley, S, Hooge, J, Jülich, D, Knaut, H, Maderspacher, F, Neumann, C, Nicolson, T, Nüsslein-Volhard, C, Roehl, H, Schönberger, U, Seiler, C, Söllner, C, Sonawane, M, Wehner, A, Weiler, C, Schmid, B, Hagner, U, Hennen, E, Kaps, C, Kirchner, A, Koblizek, TI, Langheinrich, U, Metzger, C, Nordin, R, Pezzuti, M, Schlombs, K, deSantana-Stamm, J, Trowe, T, Vacun, G, Walker, A & Weiler, C 2008, 'montalcino, A zebrafish model for variegate porphyria', Experimental Hematology, vol. 36, no. 9, pp. 1132-1142. https://doi.org/10.1016/j.exphem.2008.04.008
Dooley KA, Fraenkel PG, Langer NB, Schmid B, Davidson AJ, Weber G et al. montalcino, A zebrafish model for variegate porphyria. Experimental Hematology. 2008 Sep;36(9):1132-1142. https://doi.org/10.1016/j.exphem.2008.04.008
Dooley, Kimberly A. ; Fraenkel, Paula G. ; Langer, Nathaniel B. ; Schmid, Bettina ; Davidson, Alan J. ; Weber, Gerhard ; Chiang, Ken ; Foott, Helen ; Dwyer, Caitlin ; Wingert, Rebecca A. ; Zhou, Yi ; Paw, Barry H. ; Zon, Leonard I. ; Bebber van, F. ; Busch-Nentwich, E. ; Dahm, R. ; Frohnhöfer, H. G. ; Geiger, H. ; Gilmour, D. ; Holley, S. ; Hooge, J. ; Jülich, D. ; Knaut, H. ; Maderspacher, F. ; Neumann, C. ; Nicolson, Teresa ; Nüsslein-Volhard, C. ; Roehl, H. ; Schönberger, U. ; Seiler, C. ; Söllner, C. ; Sonawane, M. ; Wehner, A. ; Weiler, C. ; Schmid, B. ; Hagner, U. ; Hennen, E. ; Kaps, C. ; Kirchner, A. ; Koblizek, T. I. ; Langheinrich, U. ; Metzger, C. ; Nordin, R. ; Pezzuti, M. ; Schlombs, K. ; deSantana-Stamm, J. ; Trowe, T. ; Vacun, G, ; Walker, A. ; Weiler, C. / montalcino, A zebrafish model for variegate porphyria. In: Experimental Hematology. 2008 ; Vol. 36, No. 9. pp. 1132-1142.
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abstract = "Objective: Inherited or acquired mutations in the heme biosynthetic pathway leads to a debilitating class of diseases collectively known as porphyrias, with symptoms that can include anemia, cutaneous photosensitivity, and neurovisceral dysfunction. In a genetic screen for hematopoietic mutants, we isolated a zebrafish mutant, montalcino (mno), which displays hypochromic anemia and porphyria. The objective of this study was to identify the defective gene and characterize the phenotype of the zebrafish mutant. Materials and Methods: Genetic linkage analysis was utilized to identify the region harboring the mno mutation. Candidate gene analysis together with reverse transcriptase polymerase chain reaction was utilized to identify the genetic mutation, which was confirmed via allele-specific oligo hybridizations. Whole mount in situ hybridizations and o-dianisidine staining were used to characterize the phenotype of the mno mutant. mRNA and morpholino microinjections were performed to phenocopy and/or rescue the mutant phenotype. Results: Homozygous mno mutant embryos have a defect in the protoporphyrinogen oxidase (ppox) gene, which encodes the enzyme that catalyzes the oxidation of protoporphyrinogen. Homozygous mutant embryos are deficient in hemoglobin, and by 36 hours post-fertilization are visibly anemic and porphyric. The hypochromic anemia of mno embryos was partially rescued by human ppox, providing evidence for the conservation of function between human and zebrafish ppox. Conclusion: In humans, mutations in ppox result in variegate porphyria. At present, effective treatment for acute attacks requires the administration intravenous hemin and/or glucose. Thus, mno represents a powerful model for investigation, and a tool for future screens aimed at identifying chemical modifiers of variegate porphyria.",
author = "Dooley, {Kimberly A.} and Fraenkel, {Paula G.} and Langer, {Nathaniel B.} and Bettina Schmid and Davidson, {Alan J.} and Gerhard Weber and Ken Chiang and Helen Foott and Caitlin Dwyer and Wingert, {Rebecca A.} and Yi Zhou and Paw, {Barry H.} and Zon, {Leonard I.} and {Bebber van}, F. and E. Busch-Nentwich and R. Dahm and Frohnh{\"o}fer, {H. G.} and H. Geiger and D. Gilmour and S. Holley and J. Hooge and D. J{\"u}lich and H. Knaut and F. Maderspacher and C. Neumann and Teresa Nicolson and C. N{\"u}sslein-Volhard and H. Roehl and U. Sch{\"o}nberger and C. Seiler and C. S{\"o}llner and M. Sonawane and A. Wehner and C. Weiler and B. Schmid and U. Hagner and E. Hennen and C. Kaps and A. Kirchner and Koblizek, {T. I.} and U. Langheinrich and C. Metzger and R. Nordin and M. Pezzuti and K. Schlombs and J. deSantana-Stamm and T. Trowe and G, Vacun and A. Walker and C. Weiler",
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T1 - montalcino, A zebrafish model for variegate porphyria

AU - Dooley, Kimberly A.

AU - Fraenkel, Paula G.

AU - Langer, Nathaniel B.

AU - Schmid, Bettina

AU - Davidson, Alan J.

AU - Weber, Gerhard

AU - Chiang, Ken

AU - Foott, Helen

AU - Dwyer, Caitlin

AU - Wingert, Rebecca A.

AU - Zhou, Yi

AU - Paw, Barry H.

AU - Zon, Leonard I.

AU - Bebber van, F.

AU - Busch-Nentwich, E.

AU - Dahm, R.

AU - Frohnhöfer, H. G.

AU - Geiger, H.

AU - Gilmour, D.

AU - Holley, S.

AU - Hooge, J.

AU - Jülich, D.

AU - Knaut, H.

AU - Maderspacher, F.

AU - Neumann, C.

AU - Nicolson, Teresa

AU - Nüsslein-Volhard, C.

AU - Roehl, H.

AU - Schönberger, U.

AU - Seiler, C.

AU - Söllner, C.

AU - Sonawane, M.

AU - Wehner, A.

AU - Weiler, C.

AU - Schmid, B.

AU - Hagner, U.

AU - Hennen, E.

AU - Kaps, C.

AU - Kirchner, A.

AU - Koblizek, T. I.

AU - Langheinrich, U.

AU - Metzger, C.

AU - Nordin, R.

AU - Pezzuti, M.

AU - Schlombs, K.

AU - deSantana-Stamm, J.

AU - Trowe, T.

AU - Vacun, G,

AU - Walker, A.

AU - Weiler, C.

PY - 2008/9

Y1 - 2008/9

N2 - Objective: Inherited or acquired mutations in the heme biosynthetic pathway leads to a debilitating class of diseases collectively known as porphyrias, with symptoms that can include anemia, cutaneous photosensitivity, and neurovisceral dysfunction. In a genetic screen for hematopoietic mutants, we isolated a zebrafish mutant, montalcino (mno), which displays hypochromic anemia and porphyria. The objective of this study was to identify the defective gene and characterize the phenotype of the zebrafish mutant. Materials and Methods: Genetic linkage analysis was utilized to identify the region harboring the mno mutation. Candidate gene analysis together with reverse transcriptase polymerase chain reaction was utilized to identify the genetic mutation, which was confirmed via allele-specific oligo hybridizations. Whole mount in situ hybridizations and o-dianisidine staining were used to characterize the phenotype of the mno mutant. mRNA and morpholino microinjections were performed to phenocopy and/or rescue the mutant phenotype. Results: Homozygous mno mutant embryos have a defect in the protoporphyrinogen oxidase (ppox) gene, which encodes the enzyme that catalyzes the oxidation of protoporphyrinogen. Homozygous mutant embryos are deficient in hemoglobin, and by 36 hours post-fertilization are visibly anemic and porphyric. The hypochromic anemia of mno embryos was partially rescued by human ppox, providing evidence for the conservation of function between human and zebrafish ppox. Conclusion: In humans, mutations in ppox result in variegate porphyria. At present, effective treatment for acute attacks requires the administration intravenous hemin and/or glucose. Thus, mno represents a powerful model for investigation, and a tool for future screens aimed at identifying chemical modifiers of variegate porphyria.

AB - Objective: Inherited or acquired mutations in the heme biosynthetic pathway leads to a debilitating class of diseases collectively known as porphyrias, with symptoms that can include anemia, cutaneous photosensitivity, and neurovisceral dysfunction. In a genetic screen for hematopoietic mutants, we isolated a zebrafish mutant, montalcino (mno), which displays hypochromic anemia and porphyria. The objective of this study was to identify the defective gene and characterize the phenotype of the zebrafish mutant. Materials and Methods: Genetic linkage analysis was utilized to identify the region harboring the mno mutation. Candidate gene analysis together with reverse transcriptase polymerase chain reaction was utilized to identify the genetic mutation, which was confirmed via allele-specific oligo hybridizations. Whole mount in situ hybridizations and o-dianisidine staining were used to characterize the phenotype of the mno mutant. mRNA and morpholino microinjections were performed to phenocopy and/or rescue the mutant phenotype. Results: Homozygous mno mutant embryos have a defect in the protoporphyrinogen oxidase (ppox) gene, which encodes the enzyme that catalyzes the oxidation of protoporphyrinogen. Homozygous mutant embryos are deficient in hemoglobin, and by 36 hours post-fertilization are visibly anemic and porphyric. The hypochromic anemia of mno embryos was partially rescued by human ppox, providing evidence for the conservation of function between human and zebrafish ppox. Conclusion: In humans, mutations in ppox result in variegate porphyria. At present, effective treatment for acute attacks requires the administration intravenous hemin and/or glucose. Thus, mno represents a powerful model for investigation, and a tool for future screens aimed at identifying chemical modifiers of variegate porphyria.

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