The A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency

Dijk, Sabine J. van; Kooiker, Kristina B.; Mazzalupo, Stacy; Yang, Yuanzhang; Kostyukova, Alla S.; Mustacich, Debbie J.; Hoye, Elaine; Stern, Joshua A.; Kittleson, Mark D.; Harris, Samantha P.

doi:10.1016/j.abb.2016.01.006

Cited by 21 publications

(17 citation statements)

References 37 publications

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“…A research colony of mixed breed (domestic short hair) cats with HCM was generated from a single Maine Coon/mixed breed founder cat presenting with naturally-occurring disease [14,21]. To identify cats in this colony with LVOT obstruction, we used echocardiography in conscious animals to document hypertrophy (interventricular septum or left ventricular posterior wall [diastole] > 0.6 cm) and blood flow acceleration in the LVOT consistent with obstruction by continuous wave spectral Doppler, color Doppler, 2D and M-mode imaging (S2 Fig).…”

Section: Resultsmentioning

confidence: 99%

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A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy

Stern¹,

Markova²,

Ueda³

et al. 2016

PLoS ONE

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108

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Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction.

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Section: Resultsmentioning

confidence: 99%

“…Cats were obtained from a research colony of Maine Coon/mixed breed cats with heritable HCM [14,20,21]. …”

Section: Methodsmentioning

confidence: 99%

A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy

Stern¹,

Markova²,

Ueda³

et al. 2016

PLoS ONE

Self Cite

108

View full text Add to dashboard Cite

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“…A recent study also failed to identify haploinsufficiency in Maine Coon cats with the A31P mutation (van Dijk et al, 2016), indicating that a poison polypeptide mechanism may be involved in HCM due to MYBPC3 mutations in homozygous Ragdoll and Maine Coon cats. HCM not associated with MyBP-C haploinsufficiency has also been noted in some human cases with MYBPC3 mutations (Helms et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

et al. 2017

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Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model.

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“…A variant in MYBPC3, A31P, was previously linked to the development of HCM in Maine Coon cats (5). This variant occurs within the C0 domain of cardiac myosin binding protein-C (cMyBP-C), and it is expected to cause disease via structural defects in this domain, which is important for regulation of actomyosin regulation (6). Another variant in MYBPC3, A74T, has also been described across multiple cat breeds.…”

Section: Introductionmentioning

confidence: 99%

A novel homozygous premature stop mutation in TNNT2 associates with Feline cardiomyopathy

McNamara¹,

Schuckman²,

Becker³

et al. 2020

Preprint

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Background: Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart and the most common cause of sudden cardiac death in the young. HCM is considered a disease of the sarcomere owing to the large number of mutations in genes encoding sarcomeric proteins. The riddle lies in discovering how these mutations lead to disease. As a result, treatments to prevent and/or treat HCM are limited to invasive surgical myectomies or ablations. Recently, a cohort of Maine Coon cats was identified as carrying an alanine to proline substitution at amino acid 31 of the sarcomeric protein, cardiac myosin binding protein-C, encoded by MYBPC3 . Additional mutations in MYBPC3 and MYH7 have also been associated with HCM in cats. In this study, we expand the spectrum of genes associated with HCM in cats. Results: Next Generation Whole Genome sequencing was performed using DNA isolated from peripheral blood of a Maine Coon with cardiomyopathy that tested negative for the above A31P mutation. Through risk stratification of variants, we identified a novel, homozygous truncating mutation in cardiac troponin-T ( TNNT2 ), also associated with HCM in humans. Both parents tested heterozygous for the mutation, but were unaffected by the disease. Conclusions: In summary, we are the first to demonstrate the association of TNNT2 mutations and HCM in a cat, suggesting this gene should be added to the testing panel of genes when performing genetic testing for HCM in cats.

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The A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency

Cited by 21 publications

References 37 publications

A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy

A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

A novel homozygous premature stop mutation in TNNT2 associates with Feline cardiomyopathy

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