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

• Published in: Science advances Vol. 5; no. 9; p. eaax2066
• Main Authors: Ahrens-Nicklas, Rebecca C, Pappas, Christopher T, Farman, Gerrie P, Mayfield, Rachel M, Larrinaga, Tania M, Medne, Livija, Ritter, Alyssa, Krantz, Ian D, Murali, Chaya, Lin, Kimberly Y, Berger, Justin H, Yum, Sabrina W, Carreon, Chrystalle Katte, Gregorio, Carol C
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.09.2019
• Subjects: Actin Cytoskeleton - genetics; Actin Cytoskeleton - metabolism; Actin Cytoskeleton - pathology; Animals; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - pathology; Codon, Nonsense; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Diseases and Disorders; Female; Humans; Infant; Infant, Newborn; Male; Mice; Mice, Mutant Strains; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocardium - metabolism; Myocardium - pathology; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aax2066

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 ( , p.Trp398*). Leiomodins (Lmods) are actin-binding proteins that regulate actin filament assembly. While disease-causing mutations in smooth ( ) and skeletal ( ) muscle isoforms have been described, the cardiac ( ) isoform has not been previously associated with human disease. Like our patient, -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 -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.