Scientists describe mechanism for rare muscle disease

Scientists describe mechanism for rare muscle disease

(Medical Xpress) -- A team of scientists from the Friedrich Miescher Institute for Biomedical Research and the Hebrew University of Jerusalem describe in C. elegans the process leading to a rare form of Emery-Dreifuss muscular dystrophy, a disease caused by a mutation in lamin A in man. Lamin A not only gives shape to the nucleus, but here it is shown that it controls the positioning of genes in the nucleus, thereby guaranteeing proper transcription. In a paper appearing in Current Biology, the authors show that perturbation of tissue-specific gene localization leads to aberrant muscle structure and function.

In a collaborative effort between scientists at the FMI and in Israel, a disease-correlated mutation was reconstituted in the simple genetic organism, C. elegans. In the current study it is shown that the filamentous network formed by lamins is not only critical for the maintenance of nuclear shape, but it also contributes to the proper positioning of DNA, ensuring that silent genes and active genes are properly segregated in the nucleus.

Mutations in the genes that encode lamin proteins cause 14 different diseases in man, collectively termed laminopathies. These include early aging diseases and diseases that affect peripheral neurons, heart, skin, bones and muscles.

One of the diseases caused by dominant mutations in the gene encoding lamin A is Emery-Dreifuss (AD-EDMD). It is characterized by a weakening in certain skeletal muscles and early contractures at the neck, elbows and the Achilles tendons, as well as defects. How these mutations lead to the disease was largely unknown.

By manipulating the lamin gene in the worm Caenorhabditis elegans, Prof. Yosef Gruenbaum and his students Anna Mattout and Erin Bank, together with Prof. Susan Gasser and her collaborators Brietta Pike, Benjamin Towbin, Adriana Gonzalez and Peter Meister, were able to show that lamin is necessary for the positioning of regions in the DNA that are mostly inactive, so called heterochromatin.

They then introduced low levels of a lamin bearing a mutation that causes AD-EDMD in humans, into the worms and tracked their expression. In the worms expressing the mutant lamin, they detected abnormal retention of a muscle-specific gene array at the nuclear periphery. The animals expressing the mutant lamin had selectively perturbed structures of body muscle and reduced muscle function, which strongly resembled the situation in human patients.

One important conclusion of this study, which appeared today in the online edition of , is that lamin filaments help arrange silent genes at the nuclear periphery and - during normal tissue-specific activation -- allow release of the activated normal gene. A disease-linked local mutation in lamin can then impair muscle-specific reorganization of during tissue-specific promoter activation in a dominant manner. This dominance and the correlated muscle dysfunction typify, for example, Emery Dreifuss muscular dystrophy.

More information: Mattout A, Pike BL, Towbin BD, Bank EM, Gonzalez-Sandoval A, Stadler MB, Meister P, Gruenbaum Y, Gasser SM (2011) An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity, Current Biology 21 doi:10.1016/j.cub.2011.08.030 [Epub ahead of print]

Provided by Friedrich Miescher Institute for Biomedical Research

not rated yet

Related Stories

A fly lamin gene is both like and unlike human genes

Jun 13, 2007

Mitch Dushay and colleagues at Uppsala University in Sweden announce the publication of their paper, "Characterization of lamin Mutation Phenotypes in Drosophila and Comparison to Human Laminopathies" in the June 13th issue ...

Lamin A/C deficiency is 'unnerving'

Jan 05, 2009

Mutations in the nuclear intermediate filament lamin A/C (LMNA) gene are associated with Emery-Dreifuss muscular dystrophy, but cause the disease by unknown mechanisms. Méjat et al. show that one mechanism ...

Lamin B locks up Oct-1

Jan 12, 2009

A large fraction of the transcription factor Oct-1 is associated with the inner nuclear envelope, but how and why it is retained there was unknown.

Recommended for you

Doctors who helped paralysed man walk seek new patients

58 minutes ago

The Polish doctors who performed the revolutionary treatment that allowed a paralysed man to walk again said Wednesday they were looking for new candidates, as their patient described how the medical procedure has changed hi ...

Cause of ageing remains elusive

2 hours ago

A report by Chinese researchers in the journal Nature a few months ago was a small sensation: they appeared to have found the cause for why organisms age. An international team of scientists, headed by the ...

Newly discovered bacterial defence mechanism in the lungs

3 hours ago

A new study from Karolinska Institutet presents a previously unknown immunological mechanism that protects us against bacterial infections in the lungs. The study is being published in the American Journal of Respiratory an ...

Neutralising antibodies for safer organ transplants

Oct 21, 2014

Serious complications can arise following kidney transplants. If dialysis is required within the first seven days, then the transplanted organ is said to have a Delayed Graft Function (DGF), and essentially ...

User comments