Emery-Dreifuss muscular dystrophy (EDMD) is characterized by region muscle contractures, slow progressive muscle wasting and cardiomyopathy with atrioventricular conduction block. Indistinguishable forms of EDMD are inherited in autosomal dominant and X-linked manners. Mutations in emerin, an integral protein of the nuclear envelope inner membrane, cause X-linked EDMD. Autosomal dominant EDMD is caused by mutations in the LMNA gene, which encodes the nuclear envelope intermediate filament proteins lamins A and C. It is not known how mutations in nuclear envelope proteins cause muscular dystrophy. We hypothesize that mutations in these chromatin-associated proteins cause changes in the expression of genes responsible for muscle cell differentiation or survival. Our goal is to test this hypothesis using a combination of studies in transfected cells, patients' cells and tissues and animals models. In the first specific aim, we will use fluorescence microscopy and photobleaching methods to investigate how lamin A and C mutants from patients with autosomal dominant EDMD influence the mobility of emerin in the inner nuclear membrane. We will determine if mutant lamins A and C cause emerin to """"""""escape"""""""" from the inner nuclear membrane into the continuous endoplasmic reticulum. As patients with X-linked EDMD do not have emerin in the inner nuclear membrane, this finding would demonstrate a connection between the X-linked and autosomal dominant forms of the disease. In the second aim, we will use microarrays to compare gene expression in cells from patients with autosomal dominant EDMD to X-linked EDMD and Dunnigan-type partial lipodystrophy, a disease caused by mutations in different regions of lamins A and C. This will establish if emerin and lamin mutations responsible for EDMD alter expression of the same genes. We will also use microarrays to determine gene expression profiles in muscles from lamin A/C """"""""knockout"""""""" mice that develop muscular dystrophy and compare the results to what is known about pathologic alterations in gene expression in Duchenne muscular dystrophy. The results will be confirmed in tissues from human subjects with EDMD.
In Aim 3, we will generate transgenic mice expressing human lamin A mutants and determine if they develop pathological abnormalities of EDMD and similar gene expression changes. This work will help establish how abnormalities in the nuclear envelope cause muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048997-05
Application #
7231497
Study Section
Special Emphasis Panel (ZRG1-SMB (01))
Program Officer
Nuckolls, Glen H
Project Start
2003-05-15
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
5
Fiscal Year
2007
Total Cost
$301,723
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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