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Laminopathies: key components in the disease mechanism identified

07 May 2013 Helsingin yliopisto (University of Helsinki)

Laminopathies are hereditary diseases that affect mainly the muscle tissue. These diseases include for example Emery-Dreifuss Muscular dystrophy, dilated cardiomyopathy, limb-girdle muscular dystrophy and Hutchison-Gilford progeria syndrome.

The underlying defect in these diseases is mutation in the genes encoding lamins or lamin-associated proteins. For example, many mutations in the lamin gene LMNA have been associated with different diseases.

Lamins are crucial components of the nuclear lamina that underlies the inner side of nuclear envelope, and provides mechanical stability to the nucleus. Lamina also participates in many different nuclear processes.

Two theories exist, why mutations in the lamina components cause disease. According to the first theory, mutations cause changes in the nuclear structure, which can lead to cell death in tissues that undergo harsh mechanical strain, such as the muscle. The second theory postulates that disturbed lamina causes changes in the gene expression patterns that are then deleterious for the cell.

A collaborative study between American and Finnish scientists bridge these two theories. The study shows that abnormal structure of the nuclear lamina, caused by laminopathy mutations, lead to changes in gene expression by disturbing the function of a specific transcription regulating protein.

The researchers found out that in laminopathy cells, the regulation of SRF (serum response factor), which controls the expression of many important genes, is disturbed. The molecular basis for this is that LMNA mutations that cause laminopathy alter the cellular localization of emerin, which is an important constituent of the nuclear envelope. Emerin regulates actin in the cell nucleus, and actin in turn is a critical regulator of SRF activator MKL1. Therefore, mis-localized emerin in laminopathies results in reduced activation of SRF by MKL1, and reduced expression of SRF target genes. Because many SRF target genes are critical for muscle function, this finding explains, why laminopathies affect mainly this tissue type. It also gives a mechanistic link between altered nuclear envelope structure and gene expression.

This study will give a glimmer of hope to the patients suffering from laminopathies, by identifying key components that underlie the disease mechanism. Restoring MKL1 activity in laminopathies might be a productive intervention mechanism for these devastating diseases.

This study was done in collaboration between scientists from Cornell and Helsinki Universities, In Finland, the corresponding author is Maria Vartiainen from the Institute of Biotechnology, who is studying how the regulation of nuclear actin affects gene expression. In Finland, the study was funded by the Academy of Finland and Sigrid Juselius foundation.

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