The Role of A-type Lamins in Normal Cardiac Function

Abstract

A-type lamins, primarily represented by the proteins lamin A and lamin C, are unique intermediate filaments that localize to the inner nuclear membrane to form the nuclear lamina. The lamina helps maintain nuclear structure in addition to having regulatory roles in a range of nuclear processes. Point mutations in lamin A have been implicated in a wide variety of human diseases, termed laminopathies, which are categorized roughly into those affecting striated muscle tissue function, adipose tissue distribution, or pathologies associated with rapid aging in multiple tissues. The subset affecting striated muscle represents the majority of laminopathies, with patients often developing and eventually succumbing to cardiac failure resulting from progressive dilated cardiomyopathy with conduction disease. The A-type lamin knockout mouse (Lmna-/-) exhibits many characteristics of striated muscle laminopathies, such as muscular dystrophy, dilated cardiomyopathy and premature death at 6-8 weeks. In this dissertation, I use the Lmna-/- mouse model to further dissect and understand the role of lamin A in cardiac function, proposing some potential mechanisms that may be suitable for further investigation in human patients.