Myosin-binding protein-H like (MyBP-HL) truncating mutations
Cardiomyopathy and arrhythmia are diseases with significant genetic linkage. Cardiac myosin binding protein-C (cMyBP-C) is a myofilament associated protein with a C-terminal composed of repeating immunoglobulin (Ig) and fibronectin III (FnIII) domains that bind to the myosin thick filaments and titin. Truncating mutations in the C-terminal of MyBP-C prevent myofilament incorporation and resulting in degradation of the truncated protein and is a major cause of hypertrophic cardiomyopathy. Myosin-binding protein-H like (MyBP-HL) is a recently identified protein, is structurally related to cMyBP-C. Both cMyBP-C and MyBP-HL contain repeated C-terminal Ig and FnIII domains that bind to myosin. MyBP-HL is different in that it is primarily expressed in the atria where it interacts with the myofilament. A MyBP-HL premature stop mutations has been linked to ventricular conduction system abnormalities, atria enlargement, and dilated cardiomyopathy (DCM) in humans. The gnomAD database reports 9 stop gained mutations in MYBP-HL in humans including: Gln29, Trp54, Arg113, Tyr123, Trp158, Trp192, Lys250, Arg255, and Tyr307. Prior investigation modeled the MyBP-HL Arg255 mutation and showed no MyBP-HL localization to the myofilament, as seen in truncating mutations in cMyBP-C.
Atrial contraction in Atrial Fibrillation
Atrial Fibrillation is the most common cardiac rhythm disturbances and is often associated with worsening outcomes and high mortality for patients. This has made it a prominent disease to study. However, these studies center around the electrophysiology of the disease as it is currently thought to be a disease caused by problems in electrical conduction leading to irregular heartbeats. However, atrial fibrillation has been linked to a number of cardiac contractility diseases such as cardiomyopathies. This linkage to contractility diseases has piqued our interest here in the Barefield Lab to study the role of atrial contraction in atrial fibrillation. We are using a canine atrial fibrillation model to study alterations in contraction that occur with atrial fibrillation and to study molecular changes occurring at the sarcomeric level.