Growing pains

The genetics of skeletal disorders

The human genome sequence is proving a boon to researchers investigating disorders of the skeleton.

The body’s scaffolding - the skeleton - grows at a remarkable rate as we transform from a tiny baby into a full-sized adult. Whether we are destined to be tall or short the process is the same: for about 15 years, our bones will lengthen and harden until we reach our full height.

Like all tissues of the body, however, bones can be stricken by genetic disease. About one in 4000 people suffer from skeletal dysplasias, genetic disorders of the skeleton such as brittle bone disease (osteogenesis imperfecta) or dwarfism (achondroplasia).

"Skeletal dysplasias are a diverse group of diseases of about 200 different disorders," says Dr Mike Briggs, a researcher at the Wellcome Trust Centre for Cell-Matrix Research, University of Manchester. "They range from very mild disorders, which cause early-onset osteoarthritis, through forms of short-limbed and short-trunked dwarfism, to disorders that are lethal soon after birth."

Dr Briggs is investigating the causes and effects of two of the bone dysplasias: multiple epiphyseal dysplasia (MED) and pseudoachondroplasia, which vary in their severity but overlap in their outcomes. Children with mild MED are about normal height, or slightly shorter, have joint pain and stiffness in childhood and develop early-onset osteoarthritis, while pseudoachondroplasia leads to short stature and very severe early-onset osteoarthritis. "Many of the patients we see have both hips replaced by the age of 35, some even as early as 20; so even though MED can be seen as being quite a mild bone dysplasia, for the patients it’s very severe," Dr Briggs points out.

Both the joint problems and the dwarfism characteristic of these disorders are caused by disruption of the cartilage. As well as being the major compressive tissue of the joints and protecting the bones, cartilage forms the framework on which bone is laid down.

"These diseases are caused by mutations in proteins involved in building the cartilage network," says Dr Briggs. "To find the genes involved and identify the mutations causing these diseases, we collect DNA from single patients and from very large families, from all over the world."

Using the DNA from a family with several affected members, researchers can identify the region of a chromosome containing the disease gene remarkably quickly using modern equipment.

With the human genome sequence now available on the Internet, Dr Briggs can then look to see which genes are in the chromosomal region. "It’s made a big difference being able to access the public database. In the family we were working on last year, for example, there was a very good candidate gene in our chromosomal region. So we went from identifying a candidate region to finding the first mutation in a gene called matrillin-3 in about two weeks."

All the genes identified so far as being involved in MED or pseudoachondroplasia are involved in building cartilage. "Most cases of pseudoachondroplasia are caused by mutations in just one gene," says Dr Briggs. "MED, however, can be caused by a mutation in any one of six genes, but even then we can only identify mutations in about half of the MED patients we see, so there’s still a lot of work to do. Any gene involved in cartilage formation might be involved in MED."

While the gene hunting is set to continue, Dr Briggs is also looking to the future and the best ways to make use of his discoveries. "Over the next five years we need to try to understand a lot more about the disease processes," he says. "Why does a mutation in a particular gene result in a severe cartilage dysfunction? Only when we understand that can we start to think about therapies. Studying these diseases can also give us an insight into what’s happening in osteoarthritis, as it’s likely that a lot of the genes that we’re identifying in MED will have a role in general osteoarthritis."

While these may be longer-term goals, identifying the genes underlying the skeletal dysplasias is already helping to provide a definitive diagnosis for many patients. Dr Briggs is coordinator of the European Skeletal Dysplasia Network: eight labs in six EU countries that provide molecular diagnoses for these diseases free of charge. "Within six months of discovering that the matrillin-3 gene was involved in MED, we could include the gene in our diagnostic screen. It’s a way of taking cutting-edge research discoveries here in the lab and making them available to the healthcare professionals - to all of Europe in fact."

As many of the skeletal dysplasias are difficult to diagnose from symptoms alone, molecular diagnosis can often be used to confirm or discount a particular diagnosis. There are a number of complications associated with the bone dysplasias, which can affect different body functions. The complications are often unpredictable but many are diagnosis specific. Hence molecular analysis can play a valuable role not only in establishing a diagnosis and facilitating accurate genetic counselling but also assisting in clinical management of the condition.

But the clinical benefits of a definitive diagnosis may in fact be less than the positive impact it can have on a patient’s psyche. "It’s very moving at times, working with these families who have these terribly deforming diseases," says Dr Briggs. "Some patients move from doctor to doctor, getting different opinions and diagnoses. If we can make a definite molecular diagnosis and put a name to the disease, it means a lot to them."

A matrix approach

The blue hoardings around a building site in Manchester mask the foundations of a new building for the university funded in large part by the Joint Infrastructure Fund – not an uncommon sight at present. But for researchers at the Wellcome Trust Centre for Cell-Matrix Research, these foundations hold a special appeal. Instead of being spread along several of the many corridors in the massive Stopford Building, the Centre’s 21 research groups will have a new purpose-built home by the end of 2003.

“We’ve designed the new building to promote as much interaction between researchers as possible,” says Professor Martin Humphries, Director of the Centre. “Thus, the layout of the labs, offices and write-up spaces is generic, and open-plan.It is also important, however, to provide scientists with a home, and we have achieved this by grouping four to six laboratories into shared space that is under their control.”

The functions of the extracellular matrix, the meshwork that holds cells together in the body, have often been overlooked. Indeed, open a biology textbook and you’re likely to see a cartoon of a cell floating in nothing. “The reality is that, as soon as you get more than one cell in an organism, you need to organise them relative to each other,” says Professor Humphries. “A human has billions of cells, and the cells need to be organised into tissues, held in the right place or helped to move around, and allowed to communicate properly. The extracellular matrix fulfils a key role.”

The research at the Centre falls into three programmes. “In the first programme, we are investigating how interactions between cells and the matrix regulate cell signalling, and in turn how this modulates movement, growth and death. So this work has implications for diseases such as thrombosis, cancer and inflammation. In the second programme, we want to know how the matrix meshwork that lies between cells is assembled and controlled, and how it gives tissues shape, elasticity or tensile strength. With this knowledge, we can begin to engineer tissues with synthetic structures containing cells of varying differentiated status. And lastly we’re employing genetic approaches to study the whole organism, primarily to determine the role played by cell–matrix interactions during development and to identify human diseases caused by defects in matrix.”

The matrix is involved in most major human diseases, either directly, as in osteoarthritis, or indirectly, as in genetic diseases that affect the matrix. But in other cases, normal cell adhesive events are usurped by the condition. “In asthma, for example, white blood cells move into the lung, or in cancer, endothelial cells penetrate tumour tissue to create new blood vessels. The white blood cells and endothelial cells are not abnormal, but if we can find ways to stop cells adhering and migrating, we may be able to treat the diseases.”

External links

Dr Michael Briggs at the Wellcome Trust Centre for Cell-Matrix Research, University of Manchester: Research interests