Disruption of cardiac thin filament assembly arising from a mutation in : A novel mechanism of neonatal dilated cardiomyopathy
AuthorAhrens-Nicklas, Rebecca C
Pappas, Christopher T
Farman, Gerrie P
Mayfield, Rachel M
Larrinaga, Tania M
Krantz, Ian D
Lin, Kimberly Y
Berger, Justin H
Yum, Sabrina W
Carreon, Chrystalle Katte
Gregorio, Carol C
AffiliationUniv Arizona, Dept Cellular & Mol Med
Univ Arizona, Sarver Mol Cardiovasc Res Program
MetadataShow full item record
PublisherAMER ASSOC ADVANCEMENT SCIENCE
CitationR. C. Ahrens-Nicklas, C. T. Pappas, G. P. Farman, R. M. Mayfield, T. M. Larrinaga, L. Medne, A. Ritter, I. D. Krantz, C. Murali, K. Y. Lin, J. H. Berger, S. W. Yum, C. K. Carreon, C. C. Gregorio, Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy. Sci. Adv. 5, eaax2066 (2019).
RightsCopyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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AbstractNeonatal 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.
NoteOpen access journal
VersionFinal published version
SponsorsNIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01HL108625, R01HL123078, T32GM008638, T32GM07526-41]