What is the pathophysiology of Emery-Dreifuss muscular dystrophy (EDMD)?

Updated: May 23, 2019
  • Author: Eli S Neiman, DO, FACN; Chief Editor: Amy Kao, MD  more...
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In 5 of 6 gene mutations that have been shown to cause EDMD, the affected protein is present in the LINC (linker of nucleoskeleton and cytoskeleton) complex. This complex includes nuclear membrane integral and associated proteins including emerin, lamin A/C, SUN1, SUN2, nesprin-1, and nesprin-2 that are proposed to form a mechanical link between the nucleoskeleton and cytoskeleton. [1] Even though these proteins are ubiquitously expressed, disease manifestations are tissue specific for as yet unclear reasons. EDMD1 is caused by mutations in the EMD gene on the X chromosome that codes for the nuclear envelope protein emerin. Mutations occur throughout the gene and almost always result in complete absence of emerin from muscle or mislocalization of emerin. On rare occasions, a decreased amount of a modified form of emerin is produced in muscle. Emerin is a ubiquitous inner nuclear membraneprotein, presentin nearly all cell types, although its highest expression is in skeletal and cardiacmuscle.Emerin binds to many nuclear proteins, including several gene-regulatory proteins (eg, barrier-to-autointegration factor, germ cell-less, Btf), nesprins (proteins that act as molecular scaffolds), F-actin, and lamins.

EDMD2/EDMD3 is due to mutations (autosomal dominant and autosomal recessive, respectively) in the LMNA gene that codes for lamins A and C. Mutations in LMNA occur throughout the gene and can cause several different phenotypes (see Causes). Lamins are intermediate filaments found in the inner nuclear membrane and nucleoplasm of almost all cells and have multiple functions including providing mechanical strength to the nucleus, helping to determine nuclear shape, and anchoring and spacing nuclear pore complexes; they are also essential for DNA replication and mRNA transcription. They bind to structural components (emerin, nesprin), chromatin components (histone), signal transduction molecules (protein kinase C), and several gene regulatory molecules.

New mutations have been found in the synaptic nuclear envelope protein 1 (SYNE1) gene and in the synaptic nuclear envelope protein 2 (SYNE2) gene in a few families, also termed Nesprin-1 and Nesprin-2, respectively. [2] Inheritance was autosomal dominant or sporadic. Phenotypes ranged from asymptomatic to limb girdle or in one case, scapular weakness with progression to a wheelchair by age 26 years. Cardiac involvement and contractures were present in some, but not all patients.

Lastly, mutations in the transmembrane protein 43 (TMEM43), also termed LUMA, which binds to emerin and SUN2, has also been reported to cause an EDMD phenotype in a few families.

How mutations in EMD, LMNA, SYNE1, SYNE2, and TMEM43 cause EDMD is unknown. Two main hypotheses have been suggested. The first suggests that disruption of the inner nuclear membrane and the nuclear lamina causes disorganization of nuclear chromatin and gene expression, while the second proposes that the mechanical strength of the cell nucleus is disrupted when the nuclear lamina is weakened leading to structural and signaling defects in mechanically stressed tissue such as muscle and heart. Mutations in all of these genes have been shown to result in defects in the nucleoskeleton and related structures that could cause the above pathologic abnormalities.

Whatever the true mechanism, the discovery of mutations in several different nuclear membrane proteins that cause similar diseases will likely eventually lead to a better understanding of nuclear membrane physiology and the pathophysiology of diseases caused by mutations in these proteins.

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