Emery-Dreifuss muscular dystrophy (EDMD) is a syndrome that can result from mutations in several different genes, most of which encode proteins of the nuclear envelope. Skeletal muscle wasting and weakness, joint contractions and life-threatening cardiomyopathy are the classical clinical features. Autosomal EDMD results from mutations in LMNA, which encodes A-type lamins, intermediate filament proteins lining the inner nuclear membrane. Most cases of X-linked EDMD result from mutations in EMD, which encodes an integral protein of the inner nuclear membrane called emerin. Emerging human genetic data demonstrate that mutations in the gene encoding LAP1, another integral protein of the inner nuclear membrane that interacts with A-type lamins and emerin, also cause muscular dystrophy. Based on our previous research, we have devised a hypothesis regarding the pathogenesis of EDMD proposing that: 1) A-type lamins, emerin and LAP1 form a complex in the nuclear envelope that plays a critical role in striated muscle maintenance, 2) this complex regulates the MAP kinase ERK1/2 and its disruption activates this kinase and 3) the dual-specific phosphatase DUSP4 links activation of ERK1/2 to enhanced AKT-mTOR signaling, which impairs autophagy and induces metabolic defects that lead to heart and skeletal muscle pathology. Using novel murine and cellular models, we will test this hypothesis.
In Aim 1, we will use mice with genetic depletions of A-type lamins, emerin and LAP1 to test to establish that these proteins function together in striated muscle cell maintenance in vivo.
In Aim 2, we will use biochemical and biophysical methods to characterize the lamin-emerin-LAP1 complex and examine its interactions with ERK1/2 and DUSP4. We will also determine if disruption of the lamin-emerin-LAP1 complex activates ERK1/2.
In Aim 3, we will test the third part of our hypothesis by crossing mice with alterations in the lamin-emerin-LAP1 complex to mice lacking DUSP4 and determining if this reduces AKT-mTOR activity, reverses defects in autophagy, normalizes cellular energy metabolism and ameliorates pathology. From a public health standpoint, this project will provide an understanding of how mutations in different genes encoding nuclear envelope proteins cause EDMD and related myopathies and identify novel targets for therapies that could change current treatment paradigms.

Public Health Relevance

Thousands of people in the United States suffer from Emery-Dreifuss and related muscular dystrophies, inherited disorders for which there are no cures. This project will use cellular and mouse models to understand how different genetic defects can cause Emery-Dreifuss muscular dystrophies and uncover disease-causing cellular abnormalities that may be targeted by novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048997-12
Application #
9068837
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cheever, Thomas
Project Start
2002-06-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Worman, Howard J (2018) Cell signaling abnormalities in cardiomyopathy caused by lamin A/C gene mutations. Biochem Soc Trans 46:37-42
Le Dour, Caroline; Macquart, Coline; Sera, Fusako et al. (2017) Decreased WNT/?-catenin signalling contributes to the pathogenesis of dilated cardiomyopathy caused by mutations in the lamin a/C gene. Hum Mol Genet 26:333-343
Shin, Ji-Yeon; Méndez-López, Iván; Hong, Mingi et al. (2017) Lamina-associated polypeptide 1 is dispensable for embryonic myogenesis but required for postnatal skeletal muscle growth. Hum Mol Genet 26:65-78
Le Dour, Caroline; Wu, Wei; Béréziat, Véronique et al. (2017) Extracellular matrix remodeling and transforming growth factor-? signaling abnormalities induced by lamin A/C variants that cause lipodystrophy. J Lipid Res 58:151-163
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Chatzifrangkeskou, Maria; Le Dour, Caroline; Wu, Wei et al. (2016) ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene. Hum Mol Genet 25:2220-2233
Herrada, Isaline; Samson, Camille; Velours, Christophe et al. (2015) Muscular Dystrophy Mutations Impair the Nuclear Envelope Emerin Self-assembly Properties. ACS Chem Biol 10:2733-42
Worman, Howard J; Schirmer, Eric C (2015) Nuclear membrane diversity: underlying tissue-specific pathologies in disease? Curr Opin Cell Biol 34:101-12
Chang, Wakam; Worman, Howard J; Gundersen, Gregg G (2015) Accessorizing and anchoring the LINC complex for multifunctionality. J Cell Biol 208:11-22

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