Mylk3 null C57BL/6N mice develop cardiomyopathy, whereas Nnt null C57BL/6J mice do not

Author:

Williams Jack L1,Paudyal Anju2,Awad Sherine1,Nicholson James1,Grzesik Dominika1,Botta Joaquin1ORCID,Meimaridou Eirini3,Maharaj Avinaash V1ORCID,Stewart Michelle2,Tinker Andrew4,Cox Roger D5ORCID,Metherell Lou A1ORCID

Affiliation:

1. Centre for Endocrinology, William Harvey Research Institute, Charterhouse Square, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

2. Medical Research Council Harwell Institute, Mary Lyon Centre, Harwell Campus, Oxfordshire, UK

3. School of Human Sciences, London Metropolitan University, London, UK

4. William Harvey Heart Centre, William Harvey Research Institute, Charterhouse Square, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

5. Medical Research Council Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK

Abstract

The C57BL/6J and C57BL/6N mice have well-documented phenotypic and genotypic differences, including the infamous nicotinamide nucleotide transhydrogenase (Nnt) null mutation in the C57BL/6J substrain, which has been linked to cardiovascular traits in mice and cardiomyopathy in humans. To assess whether Nnt loss alone causes a cardiovascular phenotype, we investigated the C57BL/6N, C57BL/6J mice and a C57BL/6J-BAC transgenic rescuing NNT expression, at 3, 12, and 18 mo. We identified a modest dilated cardiomyopathy in the C57BL/6N mice, absent in the two B6J substrains. Immunofluorescent staining of cardiomyocytes revealed eccentric hypertrophy in these mice, with defects in sarcomere organisation. RNAseq analysis identified differential expression of a number of cardiac remodelling genes commonly associated with cardiac disease segregating with the phenotype. Variant calling from RNAseq data identified a myosin light chain kinase 3 (Mylk3) mutation in C57BL/6N mice, which abolishes MYLK3 protein expression. These results indicate the C57BL/6J Nnt-null mice do not develop cardiomyopathy; however, we identified a null mutation in Mylk3 as a credible cause of the cardiomyopathy phenotype in the C57BL/6N.

Funder

Barts charity

People Programme

Medical Research Council

Marie Sklodowska Curie Innovative Training Network programme

British Heart Foundation

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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