Human Genome Project Helps Identify Skin Disease Genes

Dr. Alain Hovnanian is head of the Molecular Dermatology Unit at the Wellcome Trust Center for Human Genetics, Oxford. His team have been using the freely available DNA sequences from the Human Genome Project to identify the genes involved in three severe inherited skin disorders...

Human Genome Project Helps Identify Skin Disease Genes

Dr. Alain Hovnanian is head of the Molecular Dermatology Unit at the Wellcome Trust Centre for Human Genetics - part of the newly opened Henry Wellcome Building for Genomic Medicine - in Oxford. His team have been using the freely available DNA sequences from the Human Genome Project to identify the genes involved in three severe inherited skin disorders - Dariers disease, Hailey-Hailey disease and Netherton Syndrome.

The symptoms of Darier's disease generally appear between the ages of 6 and 20 and can be very debilitating for patients and their families. The top layer of the skin (called the epidermis) thickens in affected individuals, and they develop itchy warty bumps that can cover various regions of the upper body and become infected. Normally, the disease has a huge impact on the quality of life of sufferers because the skin eruptions can become infected and cause an unpleasant odour. Though rare, the most serious forms of Dariers disease can lead to death.

Cells in the epidermis are normally tightly joined together by special molecular "glues" and "cables". Structures that provide one of these molecular glues, known as desmosomes, are known to be disrupted in Darier's disease, and it was always assumed that the genetic defect would be in a desmosome component.

The first major step forward in the search for the Dariers disease gene was around 7 years ago, when it was found to lie in a specific region of chromosome 12, although this area did not contain any known desmosome genes. Hovnanian's team, as part of a UK consortium*, then further narrowed down its position, after which they assembled a stretch of DNA of around two and a half million base pairs that encompassed this region.

The different DNA segments of this region could then be grown in large quantities in bacterial cells, which would allow them to identify and sequence the Darier's gene.

"This is where the HGP came into its own. We sent these genomic clones to Baylor College in the US, one of the major sequencing centres in the HGP. Once they were sequenced, we further narrowed down the region of interest using molecular genetic techniques and then searched the HGP database electronically using a computer programme obtained from the UK Human Genome Mapping Project Resource Centre (HGMP)."

Dr. Alain Hovnanian, Head of the Molecular Dermatology Unit at the Wellcome Trust Centre for Human Genetics, Oxford

Using this data and information from other databases, his team identified 10 new genes and 4 known genes that were candidates for the disease gene. They then determined whether these genes were expressed in the skin and looked for mutations in those that were. To their surprise, they found that affected family members had defects in a gene that was previously known to function mainly in the heart and skeletal muscles, where the protein it produces is called a calcium ATPase pump (ATP2A2). It turned out that ATP2A2 allowed epidermal cells to maintain calcium stores, which were important for the function of desmosomes.

Hovnanian and colleagues are now trying to work out how ATP2A2 does its job.

"I hope that our identification of the important regions in ATP2A2 and how they make it work will eventually lead to development of novel therapies for Darier's sufferers. A test for this disorder is already under development."

Dr Alain Hovnanian

"It was difficult to cope with the warty rash that covered my neck at first and then spread to other areas of my body," she said. "Other people may not appreciate the effects that skin disorders like Dariers can have on personal relationships and other areas of daily life, because the bodies of sufferers are covered by clothing."

Jennifer Davies, who runs the Dariers Disease Support Group, DARDIS, and has suffered from the disease since she was 7 years old.

Mrs Davies has a 5-year-old daughter and she is not sure whether she has passed on the condition to her daughter.

"It was always difficult to understand how the disorder could be genetic when neither of my parents had any of the symptoms of Dariers. We all hope that the work carried out by Dr. Hovnanian and his dedicated team will lead to better treatments for this very debilitating skin disorder."

Mrs Jennifer Davies

Hovnanian's team are also studying another skin disorder called Hailey-Hailey disease (also known as Benign Familial Chronic Pemphigus). Patients with this condition are usually affected between the ages of 20 and 40. They suffer from blisters that initially cover various parts of the body, such as the neck and groin, but that can progressively worsen to cover large regions of the body. The blisters can rupture and become covered by thick scabs, and can severely impair the patients' quality of life.

Because Hailey-Hailey and Dariers diseases share a number of similarities, Hovnanian, along with colleagues from Professor Anthony Monaco's group, looked for genes related to ATP2A2 on a region of chromosome 3 that was known to harbour the Hailey-Hailey gene. Using information obtained from genetic databases, including freely available HGP data, the team identified the gene responsible for the disease. It turned out that their hunch was right: the Hailey-Hailey gene encodes a new calcium pump (ATP2C1) that is present in a different region of the cell to the ATPase pump that is defective in Dariers disease. (At the same time, a competing group in the US also identified the same gene.)

Their aim now is to determine how calcium ions control how cells skin stick together and how they develop into cells with more or less specialised functions. It is hoped that this knowledge may lead to improvements in treatment for both Dariers and Hailey-Hailey diseases.

Paris-born Hovnanian, 40, trained as a senior registrar in dermatology in France.

"My interest in the field stemmed from the fact that it covers a wide range of diseases, but little was known about their molecular and genetic basis. A lot of these disorders are also very severe in children."

Dr Alain Hovnanian

Having identified the Darier's and Hailey-Hailey disease genes, Hovnanian's team recently turned their attention to a skin disorder that affects newborn children called Netherton syndrome. Patients suffering from this rare disease suffer from lifelong redness of the skin, hair abnormalities and frequent allergies, which can often manifest themselves as severe reactions.

Babies are often allergic to cows milk, and as they grow older they can develop allergies to other substances, such as peanuts and grass. In the first year of life children can be severely ill and, in the past, a number of children have died, but with improved supportive care most children now survive.

Hovnanian's team previously mapped the Netherton's gene to a region of chromosome 5, and at the beginning of this month (June) identified the gene itself. The gene encodes an inhibitor of serine proteases, dubbed SPINK5 (serine protease inhibitor Kazal type-5). Serine proteases are enzymes that chop up specific proteins. People with Netherton's syndrome have mutations in the SPINK5 gene which result in the loss of the protein's function.

"The defect in SPINK5 may explain the skin defects in Netherton's that lead to recurrent infections and inflammation. In addition, SPINK5 appears to play a novel and important role in the efficient functioning of the immune system, which may explain why Netherton's patients have defective responses to allergens."

Dr Alain Hovnanian

"The exciting thing about discovering the Netherton's gene is that it could lead to prenatal diagnosis, a possible skin test which could confirm disease, and, hopefully, the development of more specific targeted treatment. Although a rare disease, finding out more about this gene may be helpful in understanding common allergies."

Dr John Harper, Consultant in Paediatric Dermatology at Great Ormond Street Hospital

"The most exciting part of the findings is the possible development of more specific targeted treatment to improve the condition of the skin. Prenatal diagnosis is very interesting but if a carrier of Netherton's syndrome can be identified through a blood test I think it could be extremely useful."

Mandy Aldwin who is in her 20s and suffers from Netherton's syndrome

*The UK consortium involved Hovnanian's team, and Professor Tom Strachan's and Mike Owens groups in Newcastle and Cardiff, respectively.

Notes to Editors
  • Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.

    Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S et al.

    Nature genetics 1999;21;3;271-7

  • Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump.

    Sudbrak R, Brown J, Dobson-Stone C, Carter S, Ramser J et al.

    Human molecular genetics 2000;9;7;1131-40

  • Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping.

    Chavanas S, Garner C, Bodemer C, Ali M, Teillac DH et al.

    American journal of human genetics 2000;66;3;914-21

  • Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.

    Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M et al.

    Nature genetics 2000;25;2;141-2

1. Dr. Hovnanian originally studied a specific form of a disease called Dystrophic Epidermolysis Bullosa, in which the adhesion of epidermis to the dermis is prevented. The skin is so fragile that it can form severe blisters or tear when touched. The condition is present from birth and affected children suffer from malnutrition, anaemia and infections. Hovnanian was the first to establish that the severe forms of the disease were due to defects in a molecule called type VII collagen which encodes anchoring fibrils. His work on Epidermolysis Bullosa has been mainly funded by the Dystrophic Epidermolysis Bullosa Research Association (D.E.B.R.A.) UK.

2. Darier's Disease Support Group (DARDIS),
Jennifer Davies,
PO Box 36,
Milford Haven,
SA73 3YF.

3. Ichthyosis Support Group (ISG).
Pamelia Catlyn-Ranger,
16 Cambridge Court,
Cambridge Avenue,
NW6 5AB.
Tel: 020 7461 0356.

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