Cargando…

Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs

Familial Hypertrophic Cardiomyopathy (HCM) is the most common inherited cardiac disease. About 30% of the patients are heterozygous for mutations in the MYH7 gene encoding the ß-myosin heavy chain (MyHC). Hallmarks of HCM are cardiomyocyte disarray and hypertrophy of the left ventricle, the symptoms...

Descripción completa

Detalles Bibliográficos
Autores principales: Montag, J., Petersen, B., Flögel, A. K., Becker, E., Lucas-Hahn, A., Cost, G. J., Mühlfeld, C., Kraft, T., Niemann, H., Brenner, B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859159/
https://www.ncbi.nlm.nih.gov/pubmed/29555974
http://dx.doi.org/10.1038/s41598-018-22936-z
_version_ 1783307763735068672
author Montag, J.
Petersen, B.
Flögel, A. K.
Becker, E.
Lucas-Hahn, A.
Cost, G. J.
Mühlfeld, C.
Kraft, T.
Niemann, H.
Brenner, B.
author_facet Montag, J.
Petersen, B.
Flögel, A. K.
Becker, E.
Lucas-Hahn, A.
Cost, G. J.
Mühlfeld, C.
Kraft, T.
Niemann, H.
Brenner, B.
author_sort Montag, J.
collection PubMed
description Familial Hypertrophic Cardiomyopathy (HCM) is the most common inherited cardiac disease. About 30% of the patients are heterozygous for mutations in the MYH7 gene encoding the ß-myosin heavy chain (MyHC). Hallmarks of HCM are cardiomyocyte disarray and hypertrophy of the left ventricle, the symptoms range from slight arrhythmias to sudden cardiac death or heart failure. To gain insight into the underlying mechanisms of the diseases’ etiology we aimed to generate genome edited pigs with an HCM-mutation. We used TALEN-mediated genome editing and successfully introduced the HCM-point mutation R723G into the MYH7 gene of porcine fibroblasts and subsequently cloned pigs that were heterozygous for the HCM-mutation R723G. No off-target effects were determined in the R723G-pigs. Surprisingly, the animals died within 24 h post partem, probably due to heart failure as indicated by a shift in the a/ß-MyHC ratio in the left ventricle. Most interestingly, the neonatal pigs displayed features of HCM, including mild myocyte disarray, malformed nuclei, and MYH7-overexpression. The finding of HCM-specific pathology in neonatal R723G-piglets suggests a very early onset of the disease and highlights the importance of novel large animal models for studying causative mechanisms and long-term progression of human cardiac diseases.
format Online
Article
Text
id pubmed-5859159
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-58591592018-03-20 Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs Montag, J. Petersen, B. Flögel, A. K. Becker, E. Lucas-Hahn, A. Cost, G. J. Mühlfeld, C. Kraft, T. Niemann, H. Brenner, B. Sci Rep Article Familial Hypertrophic Cardiomyopathy (HCM) is the most common inherited cardiac disease. About 30% of the patients are heterozygous for mutations in the MYH7 gene encoding the ß-myosin heavy chain (MyHC). Hallmarks of HCM are cardiomyocyte disarray and hypertrophy of the left ventricle, the symptoms range from slight arrhythmias to sudden cardiac death or heart failure. To gain insight into the underlying mechanisms of the diseases’ etiology we aimed to generate genome edited pigs with an HCM-mutation. We used TALEN-mediated genome editing and successfully introduced the HCM-point mutation R723G into the MYH7 gene of porcine fibroblasts and subsequently cloned pigs that were heterozygous for the HCM-mutation R723G. No off-target effects were determined in the R723G-pigs. Surprisingly, the animals died within 24 h post partem, probably due to heart failure as indicated by a shift in the a/ß-MyHC ratio in the left ventricle. Most interestingly, the neonatal pigs displayed features of HCM, including mild myocyte disarray, malformed nuclei, and MYH7-overexpression. The finding of HCM-specific pathology in neonatal R723G-piglets suggests a very early onset of the disease and highlights the importance of novel large animal models for studying causative mechanisms and long-term progression of human cardiac diseases. Nature Publishing Group UK 2018-03-19 /pmc/articles/PMC5859159/ /pubmed/29555974 http://dx.doi.org/10.1038/s41598-018-22936-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Montag, J.
Petersen, B.
Flögel, A. K.
Becker, E.
Lucas-Hahn, A.
Cost, G. J.
Mühlfeld, C.
Kraft, T.
Niemann, H.
Brenner, B.
Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs
title Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs
title_full Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs
title_fullStr Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs
title_full_unstemmed Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs
title_short Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs
title_sort successful knock-in of hypertrophic cardiomyopathy-mutation r723g into the myh7 gene mimics hcm pathology in pigs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859159/
https://www.ncbi.nlm.nih.gov/pubmed/29555974
http://dx.doi.org/10.1038/s41598-018-22936-z
work_keys_str_mv AT montagj successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT petersenb successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT flogelak successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT beckere successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT lucashahna successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT costgj successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT muhlfeldc successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT kraftt successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT niemannh successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs
AT brennerb successfulknockinofhypertrophiccardiomyopathymutationr723gintothemyh7genemimicshcmpathologyinpigs