Disruption of cardiac thin filament assembly arising from a mutation in : A novel mechanism of neonatal dilated cardiomyopathy
Author
Ahrens-Nicklas, Rebecca CPappas, 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
Affiliation
Univ Arizona, Dept Cellular & Mol MedUniv Arizona, Sarver Mol Cardiovasc Res Program
Issue Date
2019-09-04
Metadata
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AMER ASSOC ADVANCEMENT SCIENCECitation
R. 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).Journal
SCIENCE ADVANCESRights
Copyright © 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).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.Note
Open access journalISSN
2375-2548PubMed ID
31517052Version
Final published versionSponsors
NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01HL108625, R01HL123078, T32GM008638, T32GM07526-41]ae974a485f413a2113503eed53cd6c53
10.1126/sciadv.aax2066
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Except where otherwise noted, this item's license is described as Copyright © 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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