August 30, 2000
Gene discovery leads to diagnostic test for kidney disease
An international team of researchers, including scientists from The Hospital for Sick Children (SickKids) and the University of Toronto, have identified the gene responsible for a form of kidney disease, and the corresponding diagnostic test. This research is published in the September issue of the scientific journal Nature Genetics.
A research group from Cambridge University led by Dr. Fiona Karet brought clinical data for distal renal tubular acidosis to the Centre for Applied Genomics at The Hospital for Sick Children so that the gene mutation that causes this disease could be identified. SickKids is the headquarters for the Human Genome Project’s chromosome 7 research, and it was suspected that the gene for this form of kidney disease was on chromosome 7.
"The big difference in the discovery of this gene compared with previous ones is the speed in which we were able to identify it," said Dr. Stephen Scherer, associate director of SickKids' Centre of Applied Genomics and a co-author of the study. "Five years ago it would have taken us a couple of years to identify the gene, and a year ago it would have taken at least a full year. This time, we were able to do it in less than six months, and this gene was on a region of the chromosome that we didn’t know a lot about."
The SickKids research group had sequenced the DNA of many of the genes on chromosome 7, and by matching these gene sequences with the chromosome sequences that have arisen from the Human Genome Project, they could determine the structure of the gene and then pinpoint a candidate gene relatively quickly. Using a technique called positional cloning, which was pioneered by SickKids’s geneticist-in-chief Lap-Chee Tsui, they could verify that they had the right disease gene and then develop a genetic screening test for this form of distal renal tubular acidosis (autosomal recessive without hearing loss). Jennifer Skaug, a technician in the Centre for Applied Genomics, and Jonathan Grover, a high school co-op student, contributed significantly to the gene discovery.
Distal renal tubular acidosis is a condition in which the body is in an acidic state, caused by abnormal excretion of acid (hydrogen ions) from part of the kidney (the distal tubule). The inherited forms of this condition generally present in childhood, often in infancy. Because the kidneys are unable to excrete the acid, the blood becomes too acidic. Accompanying features of this condition include urinary potassium and calcium wasting that, if left untreated, can lead to growth failure, dehydration, weakness, poor bone calcification (rickets) and deposits of calcium in the kidney (nephrocalcinosis). An early diagnosis leads to the establishment of treatment at a time when the serious effects of the condition (mentioned above) can be avoided.
"It’s really important to get clinicians involved in collecting data from patients," added Dr. Scherer, who is also an assistant professor of Molecular and Medical Genetics at the University of Toronto. "In SickKids’ Centre for Applied Genomics, we now have the infrastructure, technology and expertise, along with the information from the Human Genome Project, to do the genetic science very quickly. With the right clinical data, this enables us to develop diagnostic tests within a short period of time."
This research was supported by the Medical Research Council of Canada, the Welcome Trust in the United Kingdom, The Hospital for Sick Children Foundation, the Canada Foundation for Innovation, and the Ontario Premier’s Research Excellence Award.
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