The nuclear envelope (NE) in eukaryotic cells separates nuclear and cytoplasmic compartments. The NE is comprised of an inner nuclear membrane (INM) and an outer nuclear membrane (ONM), which are lined with numerous proteins including those of the LInker-complex between the Nucleoskeleton and the Cytoskeleton (LINC). Mutations in several LINC members cause cardiomyopathies. Luma is a newly discovered member of the LINC complex in the INM. A single amino acid substitution of serine 358 to leucine (S358L) in Luma causes an autosomal-dominant, fully penetrant, cardiomyopathy. Luma interacts with other members of the LINC complex that reside in the INM, including Emerin, Lamins, and SUN2. Luma may play a role in Emerin localization, as HeLa cells depleted of Luma by RNA interference exhibit altered localization of Emerin and a reduction in Emerin levels. Another partner of Lama, LaminA/C directly interacts with chromosomes, and mutations in Lamin result in aberrant chromosome positioning and correlated changes in gene expression. The foregoing results have led us to the hypothesis that Luma plays a key role in cardiomyocyte nucleoskeletal and cytoskeletal integrity, chromosome positioning, and gene expression, and that the S358L mutation in Luma impairs specific aspects of Luma function to lead to cardiomyopathy. Accordingly, our Specific Aims are: 1) To characterize roles of Luma in developing and adult cardiomyocytes by elucidating Luma's subcellular localization and interaction partners, and by performing detailed histological and physiological analyses of cardiac specific Luma knockout mouse models utilizing a floxed allele of Luma. 2) To elucidate molecular mechanisms underlying cardiomyopathy consequent to the S358L mutation in Luma by detailed histological and physiological analyses of a Luma S358L knock-in mouse model. 3) To investigate mechanisms by which the Luma S358L mutation impacts human cardiomyocyte function, utilizing human induced pluripotent stem cell (iPSC) and human embryonic stem cell (hESC)-derived Luma- mutant cardiomyocytes.

Public Health Relevance

While it is clear that mutations in Luma result in fully penetrant cardiomyopathy, little is known as to the role of Luma in cardiomyocytes or cardiac tissue, or how the Luma mutation leads to cardiomyopathy. Our proposed studies are aimed at understanding the role of Luma in cardiac muscle structure and function and to gain insights into mechanisms by which mutations in Luma cause cardiomyopathy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Wang, Lan-Hsiang
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Zhang, Zhiyuan; Mu, Yongxin; Veevers, Jennifer et al. (2016) Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure. Circ Heart Fail 9:
Pereira, Laëtitia; Rehmann, Holger; Lao, Dieu Hung et al. (2015) Novel Epac fluorescent ligand reveals distinct Epac1 vs. Epac2 distribution and function in cardiomyocytes. Proc Natl Acad Sci U S A 112:3991-6
Liang, Xingqun; Zhang, Qingquan; Cattaneo, Paola et al. (2015) Transcription factor ISL1 is essential for pacemaker development and function. J Clin Invest 125:3256-68
Lao, Dieu Hung; Esparza, Mary C; Bremner, Shannon N et al. (2015) Lmo7 is dispensable for skeletal muscle and cardiac function. Am J Physiol Cell Physiol 309:C470-9
Mu, Yongxin; Jing, Ran; Peter, Angela K et al. (2015) Cypher and Enigma homolog protein are essential for cardiac development and embryonic survival. J Am Heart Assoc 4:
Hashem, Sherin I; Perry, Cynthia N; Bauer, Matthieu et al. (2015) Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure. Stem Cells 33:2343-50
Mastrototaro, Giuseppina; Liang, Xingqun; Li, Xiaodong et al. (2015) Nebulette knockout mice have normal cardiac function, but show Z-line widening and up-regulation of cardiac stress markers. Cardiovasc Res 107:216-25
Sheikh, Farah; Lyon, Robert C; Chen, Ju (2015) Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease. Gene 569:14-20
Chen, Tianji; Zhou, Guofei; Zhou, Qiyuan et al. (2015) Loss of microRNA-17∼92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. Am J Respir Crit Care Med 191:678-92
Wei, Chaoliang; Qiu, Jinsong; Zhou, Yu et al. (2015) Repression of the Central Splicing Regulator RBFox2 Is Functionally Linked to Pressure Overload-Induced Heart Failure. Cell Rep :

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