Yang Q, Sanbe A, Osinska H, Hewett T E, Klevitsky R, Robbins J
Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
J Clin Invest. 1998 Oct 1;102(7):1292-300. doi: 10.1172/JCI3880.
Familial hypertrophic cardiomyopathy can be caused by mutations in genes encoding sarcomeric proteins, including the cardiac isoform of myosin binding protein C (MyBP-C), and multiple mutations which cause truncated forms of the protein to be made are linked to the disease. We have created transgenic mice in which varying amounts of a mutated MyBP-C, lacking the myosin and titin binding domains, are expressed in the heart. The transgenically encoded, truncated protein is stable but is not incorporated efficiently into the sarcomere. The transgenic muscle fibers showed a leftward shift in the pCa2+-force curve and, importantly, their power output was reduced. Additionally, expression of the mutant protein leads to decreased levels of endogenous MyBP-C, resulting in a striking pattern of sarcomere disorganization and dysgenesis.
家族性肥厚型心肌病可由编码肌节蛋白的基因突变引起，包括肌球蛋白结合蛋白C（MyBP-C）的心脏同工型，并且导致该蛋白截短形式产生的多种突变与该疾病相关。我们构建了转基因小鼠，其心脏中表达了不同量的缺失肌球蛋白和肌联蛋白结合结构域的突变型MyBP-C。转基因编码的截短蛋白是稳定的，但不能有效地整合到肌节中。转基因肌纤维的pCa2 + -力曲线向左移动，重要的是，它们的功率输出降低。此外，突变蛋白的表达导致内源性MyBP-C水平降低，从而导致肌节明显的紊乱和发育异常模式。
