The embryological basis of subclinical hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomeric proteins, the commonest being MYBPC3 encoding myosin-binding protein C. It is characterised by left ventricular hypertrophy but there is an important pre-hypertrophic phenotype with features including crypts, abnormal mitral leaflets and trabeculae. We investigated these during mouse cardiac development using high-resolution episcopic microscopy. In embryonic hearts from wildtype, homozygous (HO) and heterozygous (HET) Mybpc3-targeted knock-out (KO) mice we show that crypts (one or two) are a normal part of wildtype development but they almost all resolve by birth. By contrast, HO and HET embryos had increased crypt presence, abnormal mitral valve formation and alterations in the compaction process. In scarce normal human embryos, crypts were sometimes present. This study shows that features of the human pre-hypertrophic HCM phenotype occur in the mouse. In an animal model we demonstrate that there is an embryological HCM phenotype. Crypts are a normal part of cardiac development but, along with the mitral valve and trabeculae, their developmental trajectory is altered by the presence of HCM truncating Mybpc3 gene mutation.
UCL Biological Mass Spectrometry Laboratory, Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London, UK.
Gabriella
G
Captur
Cardiovascular Division, Brigham and Women's Hospital, Boston MA, USA.
Carolyn Y
CY
Ho
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
Saskia
S
Schlossarek
Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
Janet
J
Kerwin
INSERM U970, Paris Cardiovascular Research Center-PARCC, Paris, France.
Mariana
M
Mirabel
The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK.
Robert
R
Wilson
UCL Institute of Cardiovascular Science, University College London, Gower Street, London, UK.
Stefania
S
Rosmini
UCL Institute of Cardiovascular Science, University College London, Gower Street, London, UK.
Chinwe
C
Obianyo
University of Bordeaux, CHU de Bordeaux, CIC1401, Bordeaux, France.
Patricia
P
Reant
Biostatistics Joint Research Office, University College London, Gower Street, London, UK.
Paul
P
Bassett
UCL Institute of Cardiovascular Science, University College London, Gower Street, London, UK.
Andrew C
AC
Cook
Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
Susan
S
Lindsay
UCL Institute of Cardiovascular Science, University College London, Gower Street, London, UK.
William J
WJ
McKenna
UCL Biological Mass Spectrometry Laboratory, Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London, UK.
Kevin
K
Mills
UCL Institute of Cardiovascular Science, University College London, Gower Street, London, UK.|Barts Heart Center, The Cardiovascular Magnetic Resonance Imaging Unit and The Center for Rare Cardiovascular Diseases Unit, St Bartholomew's Hospital, West Smithfield, London, UK.
Perry M
PM
Elliott
The Francis Crick Institute Mill Hill Laboratory, The Ridgeway, Mill Hill, London, UK.
Timothy J
TJ
Mohun
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
Lucie
L
Carrier
UCL Institute of Cardiovascular Science, University College London, Gower Street, London, UK.|Barts Heart Center, The Cardiovascular Magnetic Resonance Imaging Unit and The Center for Rare Cardiovascular Diseases Unit, St Bartholomew's Hospital, West Smithfield, London, UK.
James C
JC
Moon
D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005838:Genotype; D006321:Heart / Q000196:embryology / Q000254:growth & development* / Q000503:physiopathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008943:Mitral Valve / Q000473:pathology; D009154:Mutation; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D000099163:Myosin Binding Protein C