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June 1, 1999

Researchers pinpoint region for cystic fibrosis modifier gene

TORONTO – An international team of researchers, led by Dr. Lap-Chee Tsui of The Hospital for Sick Children (SickKids) and the University of Toronto, has identified a region on chromosome 19 that contains a gene which modifies the severity of cystic fibrosis (CF). While such a modifier gene has been found in mice with cystic fibrosis, this is the first time a similar gene has been shown to exist in humans. Their research is published in the June issue of the scientific journal Nature Genetics.

"The data generated by previous SickKids research in mice led directly to this most recent discovery because there are corresponding regions in mice and humans that contain the same genes," explains Dr. Julian Zielenski, the paper’s lead author. "As a result, we knew exactly where to look in the human genome for one or more similar modifier genes."

The cystic fibrosis gene, identified in 1989 by Dr. Tsui and colleagues at SickKids and the University of Michigan, has more than 800 different mutations, all causing variations in the disease. However, not all clinical variations in cystic fibrosis can be attributed to mutations in the gene. As a result, scientists have suspected that other factors are involved, such as the activity of other genes which have a modifying effect on the disease or various environmental conditions. However, modifier genes have never been found in humans.

"The area we have pinpointed contains a gene that is involved in modifying the severity of a common intestinal obstruction in patients with cystic fibrosis," explains Dr. Zielenski. "Up to 20 percent of CF patients have this obstruction, called meconium ileus, but we’ve never been able to find a connection between a mutation in the CF gene and the development of the obstruction. Now we know that the obstruction is not caused by a specific mutation in the CF gene itself, but by the activity of a modifying gene."

Cystic fibrosis is the most common single gene disorder in the world, affecting one in every 2,000 children. In patients with CF, the secreting glands fail to function properly. Many body organs are affected, including the lungs, pancreas, liver, sweat and salivary glands, gastrointestinal tract and the male reproductive tract. The most serious symptom is a thick, dry mucus which clogs the airways and lungs and leaves the patient susceptible to chronic lung infections. Many CF patients also suffer from pancreatic malfunction, which leads to poor digestion and prevents the absorption of sufficient dietary fat. The majority of patients with CF succumb to severe lung infections before age 30.

The identification of modifier genes in CF will allow doctors to gain a better understanding of the different clinical presentations of the disease. It’s anticipated that this knowledge will lead to insights into prognosis and management of cystic fibrosis, as well as development of novel therapies.

The research was funded by the National Institutes of Health, the Canadian Genetic Diseases Network, the National Centre for Research, and The Hospital for Sick Children Foundation.

For more information, please contact:

Public Affairs
The Hospital for Sick Children
555 University Avenue
Suite 1742, Public Affairs, First floor Atrium
Toronto, ON
M5G 1X8
Canada
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Fax: 416-813-5328