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SickKids Hospital researchers identify gene for Shwachman-Diamond Syndrome

TORONTO  December 2002- Researchers at The Hospital for Sick Children (SICKKIDS) and the University of Toronto (U of T) have identified the gene that is altered in Shwachman-Diamond syndrome. The researchers studied 250 Shwachman-Diamond syndrome families from around the world and identified two major disease-causing mutations in a gene on chromosome 7. This research is reported in the January issue of the scientific journal Nature Genetics.

Shwachman-Diamond syndrome (SDS) is a relatively rare genetic disorder that occurs in approximately one in 50,000 births. SDS affects many organs in the body. Primary features of SDS include a defect in the pancreas that leads to difficulties in digesting food, hematologic (blood) problems with inadequate production of some types of white blood cells, skeletal abnormalities, and short stature. The hematologic problems make people with SDS prone to severe, sometimes fatal infections, and some die from blood complications such as leukemia or bone marrow failure.

"The identification of the gene is important because it will allow for accurate diagnosis and screening of Shwachman-Diamond syndrome. It will also help us to determine what goes wrong at the molecular level, and this will open the door to the development of new therapies," said Dr. Johanna Rommens, the study's principal investigator, an SICKKIDS senior scientist and associate professor of Molecular and Medical Genetics at U of T.

"This discovery will aid in the clinical management of Shwachman-Diamond syndrome," said Dr. Peter Durie, co-principal investigator of the study, an SICKKIDS gastroenterologist and senior scientist, and a professor of Paediatrics at U of T. "It is also very important to the families affected by this disease. We have received patient samples from around the world, and the Shwachman-Diamond parent groups from many countries supported this research financially."

Shwachman-Diamond syndrome is an autosomal recessive disease, meaning that a child needs to inherit two mutated genes (one from each parent) in order to have the disease. The SDS gene resides in a region of the human genome that was very difficult to map because it contains a lot of highly repetitious DNA sequence. It was found that in the normal state, every chromosome 7 has two copies of the SDS gene - a functional gene and a non-functional gene relic, called a 'pseudogene'.

"We have determined that the type of genetic mutation that causes Shwachman-Diamond syndrome is gene conversion, in that a piece of the non-functional pseudogene has been introduced into the good copy of the gene, thus disrupting its function. These types of mutations have been seen in more than 90 per cent of SDS patients," said Graeme Boocock, the study's lead author and a University of Toronto graduate student. Boocock is a recipient of a Canadian Institutes of Health Research doctoral research award.

Other members of the research team are Jodi Morrison, Maja Popovic, Nicole Richards, and Lynda Ellis, all from The Hospital for Sick Children.

This research was supported by the Canadian Institutes of Health Research, Shwachman-Diamond Syndrome Canada, Shwachman-Diamond Syndrome International, Shwachman-Diamond Support of Great Britain, The Harrison Wright Appeal, Shwachman-Diamond Syndrome Support of Australia, Paediatric Consultants Inc., Canadian Genetic Diseases Network of Centres of Excellence, and The Hospital for Sick Children Foundation.

The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health.

DNA sequence of chromosome 7 decoded - Canadian-led project generates database with medical annotation available to the public

TORONTO - Scientists at The Hospital for Sick Children (SickKids) have compiled the complete DNA sequence of human chromosome 7 and decoded nearly all of the genes on this medically important portion of the human genome. The research, which involved an international collaboration of 90 scientists from 10 countries, publishes in the online version of the scientific journal Science on April 10, 2003.

Two years ago, a draft (or fragmented) human genome DNA sequence was published by the public Human Genome Project, and separately by Celera Genomics. To coincide with celebrations of the 50th anniversary of the discovery of the structure of DNA, the DNA sequencing phase of the Human Genome Project will be declared completed in April.

"In a massive study, we combined all information in public and private databases, including data generated by Celera Genomics, as well 15 years of our data and analyses to generate what we believe is the most comprehensive description of any human chromosome. Chromosome 7 is often referred to as 'Canada's chromosome' because of this country's major contribution to the mapping and identification of many important disease genes on that chromosome over many years," said the study's lead author Dr. Stephen Scherer, a senior scientist at The Hospital for Sick Children and an associate professor in the Department of Molecular and Medical Genetics at the University of Toronto (U of T).

"This is the first time that a significant effort has been made to incorporate medical observations with DNA sequence as part of genomic research, which will make it accessible and useful to health-care professionals and researchers outside of the genomics field," said Dr. Johanna Rommens, a study co-author, interim head of the Genetics and Genomic Biology Research Program at SickKids, and an associate professor in the Department of Molecular and Medical Genetics at U of T.

There are 23 pairs of chromosomes in the human genome and each person inherits one of each set from their parents. The chromosomes encode genes that control all aspects of human development including some behavioural characteristics.

This study revealed that chromosome 7 contains 158 million nucleotides of DNA (5 per cent of the genome) and 1,455 genes (of the estimated 28,000 protein-coding genes in the human genome), some of which cause diseases such as cystic fibrosis, leukemia, and autism. The project also describes discoveries of sites along the chromosome where invading viruses integrate, 'fragile' regions prone to breakage, areas called 'gene jungles' and 'gene deserts', as well as primate-specific genes.

In the study, all medically relevant landmarks along the chromosome were identified, including the several hundred chromosome breakpoints where disease-related mutations occur. The breakpoints found in autism patients were used to pinpoint specific genes associated with the disorder.

The information generated by the chromosome 7 project has been established in a publicly accessible database that can be used to facilitate disease gene research. For example, a physician can enter the genetic deletions found in a patient and the known phenotypes (manifestations of the genetic mutation) are identified. The chromosome 7 database is available at www.chr7.org.

Dr. Martin Godbout, president and CEO of Genome Canada said, "This work represents an unprecedented Canadian contribution to the Human Genome Project. More importantly, it exemplifies how genetic, genomic, and clinician scientists in the public and private sectors worldwide can work together in a common goal to understand the human genome and its role in health and disease."

Mutations in the SBDS gene have been identified in about 90 percent of people with the characteristic features of Shwachman-Diamond syndrome. This gene provides instructions for making a protein whose function is unknown, although it is active in cells throughout the body. Researchers suspect that the SBDS protein may play a role in processing RNA (a molecule that is a chemical cousin of DNA). This protein may also be involved in building ribosomes, which are cellular structures that process the cell's genetic instructions to create proteins. It is unclear how SBDS mutations lead to the major signs and symptoms of Shwachman-Diamond syndrome.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.