Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. / Al-Mashhadi, Rozh Husain; Sørensen, Charlotte Brandt; Kragh, Peter M.; Christoffersen, Christina; Mortensen, Martin Bødtker; Tolbod, Lars Poulsen; Thim, Troels; Du, Yutao; Li, Juan; Liu, Ying; Moldt, Brian; Schmidt, Mette; Vajta, Gabor; Larsen, Torben; Purup, Stig; Bolund, Lars; Nielsen, Lars Bo; Callesen, Henrik; Falk, Erling; Mikkelsen, Jacob Giehm; Bentzon, Jacob Fog.

In: Science Translational Medicine, Vol. 5, No. 166, 166ra1, 2013.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Al-Mashhadi, RH, Sørensen, CB, Kragh, PM, Christoffersen, C, Mortensen, MB, Tolbod, LP, Thim, T, Du, Y, Li, J, Liu, Y, Moldt, B, Schmidt, M, Vajta, G, Larsen, T, Purup, S, Bolund, L, Nielsen, LB, Callesen, H, Falk, E, Mikkelsen, JG & Bentzon, JF 2013, 'Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant', Science Translational Medicine, vol. 5, no. 166, 166ra1. https://doi.org/10.1126/scitranslmed.3004853

APA

Al-Mashhadi, R. H., Sørensen, C. B., Kragh, P. M., Christoffersen, C., Mortensen, M. B., Tolbod, L. P., Thim, T., Du, Y., Li, J., Liu, Y., Moldt, B., Schmidt, M., Vajta, G., Larsen, T., Purup, S., Bolund, L., Nielsen, L. B., Callesen, H., Falk, E., ... Bentzon, J. F. (2013). Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Science Translational Medicine, 5(166), [166ra1]. https://doi.org/10.1126/scitranslmed.3004853

Vancouver

Al-Mashhadi RH, Sørensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP et al. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Science Translational Medicine. 2013;5(166). 166ra1. https://doi.org/10.1126/scitranslmed.3004853

Author

Al-Mashhadi, Rozh Husain ; Sørensen, Charlotte Brandt ; Kragh, Peter M. ; Christoffersen, Christina ; Mortensen, Martin Bødtker ; Tolbod, Lars Poulsen ; Thim, Troels ; Du, Yutao ; Li, Juan ; Liu, Ying ; Moldt, Brian ; Schmidt, Mette ; Vajta, Gabor ; Larsen, Torben ; Purup, Stig ; Bolund, Lars ; Nielsen, Lars Bo ; Callesen, Henrik ; Falk, Erling ; Mikkelsen, Jacob Giehm ; Bentzon, Jacob Fog. / Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. In: Science Translational Medicine. 2013 ; Vol. 5, No. 166.

Bibtex

@article{6e4a5a4b06484523807f9bb08921f747,
title = "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant",
abstract = "Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.",
keywords = "Animals, Animals, Genetically Modified, Atherosclerosis, Cloning, Organism, DNA, Disease Models, Animal, Female, Humans, Hypercholesterolemia, Hyperlipoproteinemia Type II, Liver, Male, Mutation, Phenotype, Proprotein Convertases, RNA, Messenger, Receptors, LDL, Serine Endopeptidases, Swine, Swine, Miniature, Transgenes",
author = "Al-Mashhadi, {Rozh Husain} and S{\o}rensen, {Charlotte Brandt} and Kragh, {Peter M.} and Christina Christoffersen and Mortensen, {Martin B{\o}dtker} and Tolbod, {Lars Poulsen} and Troels Thim and Yutao Du and Juan Li and Ying Liu and Brian Moldt and Mette Schmidt and Gabor Vajta and Torben Larsen and Stig Purup and Lars Bolund and Nielsen, {Lars Bo} and Henrik Callesen and Erling Falk and Mikkelsen, {Jacob Giehm} and Bentzon, {Jacob Fog}",
year = "2013",
doi = "10.1126/scitranslmed.3004853",
language = "English",
volume = "5",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "american association for the advancement of science",
number = "166",

}

RIS

TY - JOUR

T1 - Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant

AU - Al-Mashhadi, Rozh Husain

AU - Sørensen, Charlotte Brandt

AU - Kragh, Peter M.

AU - Christoffersen, Christina

AU - Mortensen, Martin Bødtker

AU - Tolbod, Lars Poulsen

AU - Thim, Troels

AU - Du, Yutao

AU - Li, Juan

AU - Liu, Ying

AU - Moldt, Brian

AU - Schmidt, Mette

AU - Vajta, Gabor

AU - Larsen, Torben

AU - Purup, Stig

AU - Bolund, Lars

AU - Nielsen, Lars Bo

AU - Callesen, Henrik

AU - Falk, Erling

AU - Mikkelsen, Jacob Giehm

AU - Bentzon, Jacob Fog

PY - 2013

Y1 - 2013

N2 - Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.

AB - Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.

KW - Animals

KW - Animals, Genetically Modified

KW - Atherosclerosis

KW - Cloning, Organism

KW - DNA

KW - Disease Models, Animal

KW - Female

KW - Humans

KW - Hypercholesterolemia

KW - Hyperlipoproteinemia Type II

KW - Liver

KW - Male

KW - Mutation

KW - Phenotype

KW - Proprotein Convertases

KW - RNA, Messenger

KW - Receptors, LDL

KW - Serine Endopeptidases

KW - Swine

KW - Swine, Miniature

KW - Transgenes

U2 - 10.1126/scitranslmed.3004853

DO - 10.1126/scitranslmed.3004853

M3 - Journal article

C2 - 23283366

VL - 5

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 166

M1 - 166ra1

ER -

ID: 137357549