Understanding the molecular causes of facioscapulohumeral muscular dystrophy

Prof Jane Hewitt

In this PhD studentship, Professor Jane Hewitt and her student, Andreas Leidenroth investigated the causes and mechanisms of facioscapulohumeral muscular dystrophy (FSH). They made some important discoveries about the DUX4 gene and the protein encoded by it, as well as showing that mutations in a gene called SMCHD1 can cause FSH. This work is fundamental to our understanding of FSH and increases our understanding of the condition which will be essential to developing therapies for it in the future.

What were the researchers aiming to do?

Facioscapulohumeral muscular dystrophy (FSH) is a muscle-wasting condition affecting mainly the facial (facio), shoulder blade (scapulo) and upper arm (humeral) muscles. The legs can also be affected. There are two types of FSH; FSH1 and FSH2. Both conditions have similar symptoms but the genetic causes differ.

FSH1 is caused by a deletion within a repeated sequence of DNA called D4Z4 on chromosome 4. Healthy individuals have between 11 and 100 copies of the repeated sequence but individuals who are affected by FSH1 have between 1 and 10 copies. The deletion can be identified by a genetic test. Researchers believed that a deletion of the repeats could lead to the incorrect production of a protein called DUX4. However, little was known about the DUX4 gene and the function of DUX4 protein, and a large focus of this research project was to investigate this.

FSH2 is caused by a different genetic mutation to FSH1; people with FSH2 do not have a D4Z4 deletion. Identifying the mutation causing FSH2 was therefore another aim of the project.

What did their research show?

To investigate the DUX4 gene and function of the DUX4 protein, the gene was expressed in high amounts in cells grown in the laboratory. However, this was found to be toxic to the cells and many died. In order to study the possible functions of DUX4 protein in live cells, the researchers developed a way of expressing the gene in lower amounts. When this was done, the DUX4 protein was found to interact with a gene called PITX1. Other groups have found the PITX1 protein to be present in higher amounts in FSH and this suggests there is a possible link between the DUX4 gene, PITX1 and FSH.

The researchers also investigated whether the DUX4 gene was found in other animals. This is useful to know as animals are often used in the laboratory for modeling human conditions and to aid understanding of the roles of specific genes. For example, the function of a gene can be better understood by deleting it and studying the consequences in the animal. The researchers showed that although the DUX4 gene was found in some animals of African origin, eg elephants, it was not found in mice, frogs and fish. This is significant because these are some of the most widely used animal models, but will be less useful for studying FSH1 due to their lack of the DUX4 gene. This information will help researchers develop animal models of FSH, which could be used to investigate the function of the DUX4 protein and the role it plays in FSH, and to test potential therapeutic approaches.

To identify the genetic changes that cause FSH2, the researchers screened blood samples from patients with FSH2 and unaffected individuals and looked for changes in the DNA. A mutation in a gene called SMCHD1 was identified and this confirmed findings from another research group in the Netherlands who had also recently discovered the mutation.

The gene carries the genetic blueprint for a protein called Structural Maintenance of Chromosomes Flexible Hinge containing 1, or SMCHD1 for short. This protein helps cells to control which genes are active, and one of the genes it helps to control is DUX4. Mutations in the SMCHD1 gene can therefore lead to the abnormal production of DUX4 which can lead to FSH muscular dystrophy.

What are the next steps?

Future work for the researchers will include completing the analysis of the data from the genetic screen. They will also investigate whether the SMCHD1 gene interacts with the DUX4 gene in various organisms to better understand how it causes FSH2.

How will the outcomes of the research benefit patients?

There is currently no treatment for FSH and there has been little progress in this area. This is mainly due to the lack of understanding about the complex and unique nature of the underlying mutation. Findings from this research provide fundamental information about the mechanisms of FSH and the genetic mutations that cause it. This will be useful for identifying targets for potential therapeutic intervention in the future.

Grant information

Project Leader: Professor Jane Hewitt
Location: University of Nottingham
Condition: Facioscapulohumeral muscular dystrophy
Duration: 4 years, completed September 2013
Total Project Cost: £98,280
Official Title: Investigation of molecular mechanisms in facioscapulohumeral muscular dystrophy

Further information and links

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