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Laminopathies: Key components in disease mechanism identified

A collaborative study between American and Finnish scientists has shown that an abnormal structure of the nuclear lamina, caused by laminopathy mutations, leads to changes in gene expression by disturbing the function of a specific transcription-regulating protein. The study was funded by the Academy of Finland, among others.

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 the nuclear envelope and provides mechanical stability to the nucleus. The 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 strains, such as the muscle. The second theory postulates that the disturbed lamina causes changes in the gene expression patterns that are thus deleterious for the cell.

A collaborative study between American and Finnish scientists bridges these two theories in a paper that will appear as an Advance Online Publication (AOP) of Nature at www.nature.com/nature on 5 May 2013.

The study shows that an abnormal structure of the nuclear lamina, caused by laminopathy mutations, leads 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 localisation 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 the SRF activator MKL1. Therefore, mislocalised emerin in laminopathies results in a reduced activation of SRF by MKL1 and a 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 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.

The study was done in collaboration between scientists from Cornell University and the University of Helsinki. The principal author in Finland is Academy Research Fellow 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 the Sigrid Juselius Foundation.

Source: University of Helsinki press release

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