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June 1, 1999

Gene found for rare metabolic disorder

TORONTO -- Scientists at The Hospital for Sick Children (SickKids), University of Toronto (U of T), and colleagues in Japan have identified a gene which causes a metabolic disorder affecting the liver. The adult-onset version of the disorder, called type II citrullinemia, is caused by an amino acid deficiency and can lead to severe liver damage and even death. The research is published in the June issue of the journal Nature Genetics.

"Working with our Japanese collaborators we were able to identify more than 100 families with a history of citrullinemia and establish that the disease-causing gene was located on human chromosome 7," explains SickKids scientist Dr. Steve Scherer, who is an assistant professor of Molecular and Medical Genetics at the U of T. "We then used the technique of positional cloning, pioneered at SickKids by study co-author Dr. Lap-Chee Tsui, to identify the defective gene which causes citrullinemia."

Most patients with type II citrullinemia suffer neurological symptoms such as disorientation, tremor and coma, and a majority of patients die within a few years after onset of the symptoms. Until the present study, the late onset form of the disease was not even established as a well-defined clinical entity, which complicated accurate diagnosis.

"Since liver transplantation can apparently lead to complete recovery from both the metabolic and neurological effects of citrullinemia, an early and proper diagnosis based on biochemical and genetic data is essential," says Dr. Scherer. "Ultimately, it is hoped that the discovery of the disease gene will lead to a simpler and less intrusive method of treatment which might include protein or gene replacement."

Type II citrullinemia is most common in Japan, where one person in 100,000 has the disorder. Cases have also been found in Europe, the USA, China, and Canada. The disease is inherited in an autosomal recessive manner (both parents must carry the defective gene and pass it on to their offspring for the child to be affected).

Dr. Scherer and Dr. Tsui led the SickKids research team, which included David Sinasac, Dr. Andrew Boright, Michael Crackower, and Jeff Lee. Drs. Keiko Kobayashi and Takeyori Saheki of Kagoshima University headed the Japanese effort. The current study arises from the SickKids group’s human chromosome 7 research, which is part of the international Human Genome Project (HGP). The HGP aims to decipher and understand all of the genes in human DNA. The work was carried out in the Centre for Applied Genomics at SickKids, which conducts research focused on DNA sequencing and chromosome mapping, disease gene discovery, functional genomics, and bioinformatics.

This research was supported by the Medical Research Council of Canada, The Hospital for Sick Children Foundation, the Ministry of Education, Science and Culture in Japan and the Kodama Foundation for Research in Medical Science.

For more information, please contact:

Public Affairs
The Hospital for Sick Children
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Suite 1742, Public Affairs, First floor Atrium
Toronto, ON
M5G 1X8
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