TITLE:
Feline Hypertrophic Cardiomyopathy Associated with the p.A31P Mutation in cMyBP-C Is Caused by Production of Mutated cMyBP-C with Reduced Binding to Actin
AUTHORS:
Mia T. N. Godiksen, Craig Kinnear, Tina Ravnsborg, Peter Højrup, Sara Granström, Inga A. Laursen, Paula L. Hedley, Johanna C. Moolman-Smook, William J. McKenna, Jørgen Koch, Michael Christiansen
KEYWORDS:
Feline; HCM; cMyBP-C; Mutation; Actin; Y2H; MSMS
JOURNAL NAME:
Open Journal of Veterinary Medicine,
Vol.3 No.2,
June
6,
2013
ABSTRACT:
Hypertrophic cardiomyopathy (HCM) is a
myocardial disorder, with complications including heart failure, thromboemboli
and sudden death. Human and feline HCM (fHCM) are clinically comparable, thus
fHCM may serve as a spontaneous animal model. fHCM in Maine Coon (MC) cats is
associated with the p.A31P mutation in the cMyBP-C protein. The mutation is
located in the cMyBP-C C0-domain which is known to interact with actin. The
presence and levels of the wild type and mutated protein in heart tissue from
mutant and wild type MC cats were examined by SDS-PAGE and mass spectrometry
(MS). Quantitative yeast-2-hybrid (Y2H) protein-protein interaction analysis
was used to assess the effect of the mutation on C0C1/actin interaction. The NMR-based structure of the
C0 domain was used to calculate the energetic consequence of replacing alanine
with a proline residue. In the homozygous MC cat, the mutated cMyBP-C
protein was present, and cMyBPC-C levels were not reduced compared to that of
the wild type cat. However, the interaction of actin with mutant cMyBP-C C0C1 was reduced compared to that of wild
type. This may be because the substitution of the alanine with proline in
position 31 was energetically highly unfavorable and resulted in only one
hydrogen bond within the anti-parallel beta-strand compared to two hydrogen-bonds
for alanine, possibly destabilizing the structure of the actin-interacting
domain. The p.A31P mutation is present in cardiac tissue and the most likely
pathogenic mechanism is interference with contractility by reducing binding of
the C0C1 domain of
cMyBP-C to actin.