Disruption of cardiac thin filament assembly arising from a mutation in LMOD2 : A novel mechanism of neonatal dilated cardiomyopathy

Abstract

Neonatal heart failure is a rare, poorly-understood presentation of familial dilated cardiomyopathy (DCM). Exome sequencing in a neonate with severe DCM revealed a homozygous nonsense variant in leiomodin 2 (LMOD2, p.Trp398*). Leiomodins (Lmods) are actin-binding proteins that regulate actin filament assembly. While disease-causing mutations in smooth (LMOD1) and skeletal (LMOD3) muscle isoforms have been described, the cardiac (LMOD2) isoform has not been previously associated with human disease. Like our patient, Lmod2-null mice have severe early-onset DCM and die before weaning. The infant’s explanted heart showed extraordinarily short thin filaments with isolated cardiomyocytes displaying a large reduction in maximum calcium-activated force production. The lack of extracardiac symptoms in Lmod2-null mice, and remarkable morphological and functional similarities between the patient and mouse model informed the decision to pursue cardiac transplantation in the patient. To our knowledge, this is the first report of aberrant cardiac thin filament assembly associated with human cardiomyopathy.

Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle

“…The thin filament is an essential component of the sarcomere (contractile unit of muscle) where it anchors in the Z-disk (barbed-end), extends toward the middle of the sarcomere (pointed-end), and overlaps with myosin-containing thick filaments. How thin-filament length (TFL) is controlled needs to be well understood as TFL dysregulation is known to occur in various myopathies (1)(2)(3). In skeletal muscle, the thin filament comprises filamentous actin (F-actin), regulatory proteins (4), capping proteins (2) and, importantly, nebulin (5).…”

Leiomodin creates a leaky cap at the pointed end of actin-thin filaments

“…In striated muscles, optimal length of actin-thin filaments is a critical factor for efficient contractile activity, and alterations in thin filament lengths are linked to devastating human skeletal and cardiac muscle diseases. Mutations interfering with the regulation of thin filament length are associated with nemaline myopathy [ 3 , 4 ] and dilated cardiomyopathy [ 5 , 6 ]. The mechanisms and important players required for thin filament length regulation are not fully identified (e.g., [ 7 ]).…”

CAP2 is a regulator of actin pointed end dynamics and myofibrillogenesis in cardiac muscle

“…Maintenance of thin filament structure is critical for its interaction with thick filaments and for the length–tension relationship during muscle contraction 49 . Regulation of actin filament dynamics, especially at the pointed end, is of great importance, since alterations in TFLs occur at this end of the filament in striated muscle 2 and are linked to life-threatening myopathies in humans 3 – 6 . Therefore, identifying protein components at pointed ends is important to better understand thin filament regulation and function.…”

“…Although the mechanisms underlying regulation of α-actin exchange and thin filament assembly are largely unknown, it is known that regulation of filament lengths is accomplished by modulation of actin polymerization at the pointed end of thin filaments in striated muscle 2 . Alterations in thin filament lengths (TFLs) are linked to the development of human muscular diseases including dilated cardiomyopathy (DCM) and nemaline myopathy 3 – 6 . Members of the tropomodulin family are the only proteins known to localize and exclusively function at thin filament pointed ends in mammalian muscle, with tropomodulin 1 (Tmod1) and leiomodin 2 (Lmod2) as the major isoforms expressed in cardiac tissue 7 – 10 .…”