Novel insights into the disease etiology of laminopathies

Abstract

Laminopathies are a heterogeneous group of diseases that are caused by mutations in the nuclear envelope proteins lamins A and C. Laminopathies include dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and familial partial lipodystrophy. Despite their near-ubiquitous expression, most laminopathies involve highly tissue-specific phenotypes, often affecting skeletal and cardiac muscle. The underlying mechanism(s) remain incompletely understood. We recently reported that altered actin dynamics in lamin A/C-deficient and mutant cells disturb nuclear shuttling of the transcriptional co-activator MKL1, which is critical for cardiac function. Expression of the inner nuclear membrane protein emerin rescues MKL1 translocation through modulating actin dynamics. Here, we elaborate on these findings, discuss new insights into the role of nuclear actin in MKL1activity, and demonstrate that primary human skin fibroblasts from a patient with dilated cardiomyopathy have impaired MKL1 nuclear translocation. These findings further strengthen the relevance of impaired MKL1 signaling as a potential contributor to the disease mechanism in laminopathies.

Keywords: :

• lamin
• MKL1
• MAL
• MRTF-A
• dilated cardiomyopathy
• nuclear actin
• mechanotransduction

This article refers to:

10.4161/rdis.27002

Citation: Ho CY, Jaalouk DE, Lammerding J. Novel insights into the disease etiology of laminopathies. Rare Diseases 2013; 1:e27002;

Addendum to:

Disclosure of potential conflicts of interest

The authors declare that no conflicts of interest exist.

Acknowledgments

We thank Dr Colin Stewart for providing the mouse models and mouse cell lines. The LMNA K219T/+ patient fibroblasts were kindly provided by Dr Gianluigi Condorelli (University of Milan, Italy). The LMNA R482Q and LMNA ΔK32 mutant cells were generated in the laboratory of Dr Gisele Bonne (Institut de Myologie, France) and graciously provided by Drs Antoine Muchir and Howard Worman (Columbia University).

This work was supported by National Institutes of Health awards [R01 NS059348 and R01 HL082792]; the Department of Defense Breast Cancer Idea Award [BC102152]; a National Science Foundation CAREER award to Lammerding J [CBET-1254846]; an award from the Progeria Research Foundation [PRF2011–0035]; postdoctoral fellowships from the American Heart Association to Jaalouk DE [AHA 09POST2320042] and to Ho CY. [AHA 13POST16740004]; a Faculty Development Grant from AUB to Jaalouk DE; and a Pilot Project Award by the Cornell Center on the Microenvironment & Metastasis through Award Number U54CA143876 from the National Cancer Institute. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.