It is significantly harder to look for problems in this part of DNA as it is not that obvious what is disease-relevant and what is not, but at least now we have a good precedent on how to tackle it and how to deal with it when we find it.
Professor Jozef Gecz
The root cause of a rare condition that has been plaguing an Australian family for 40 years and occupying a team of researchers at the University of Adelaide
for ten years has finally been found. The findings are reported in this month’s edition of the American Journal of Human Genetics
Non-syndromic intellectual disability is linked with developmental delays, epilepsy, schizophrenia and other problems. It results in lower IQ and memory, but autism and aggressive behaviour are also displayed by many affected members of the 100-strong family involved in this study. The condition can be passed on by women to their children, but symptoms appear only in male family members.
questioned lead author of the study Professor Jozef Gecz, from the University of Adelaide’s School of Pediatrics and Reproductive Health about the work he, his colleagues and students have been carrying out to determine the physiological origins of the condition.
"Biochemical, clinical and other investigations did not lead anywhere, apart perhaps from telling us that there was something unusual about this large family," Professor Gecz began. "So, after having spent ten years of our own time studying the family, we embarked on looking at gene and protein regulation, or control, rather than gene and protein structure."
Although many intellectual disabilities are a direct result of genetic mutations, it was in their examination of gene and protein regulation that the researchers found a much-needed lead. Genetic screening of family members and laboratory tests in mice revealed that the host cell factor C1 (HCFC1) is responsible for production of the protein which causes the condition. Specifically, the cells produce about 1.6 times more protein than is 'normal'.
"For many proteins such an excess does not cause any problems or can even be beneficial," Professor Gecz explained. "In this case, however, it is not good at all. We also demonstrated the negative effects by studying mouse neuronsin vitro
. Neurons just do not look like 'happy neurons' when they have slightly more of this protein. They do not branch nicely and they do not connect or communicate well."
According to Professor Gecz, it took three years for the research team to convince themselves that protein regulation was indeed the deciding factor. Pinpointing the cause means that genetic screening can be made available for women to ascertain whether they are carriers or not, and hopefully provide other benefits to sufferers in the long-term.
"That it was a regulatory problem was a surprise, but given that no structural problem could be found we were logically heading towards that explanation. While about two per cent of our genome – our DNA – codes for the 'structural' building blocks (ie, proteins), up to 80 per cent of the genome has a regulatory or controlling function.
"The balance is heavily in favour of regulatory DNA and yet, as a scientific community, we know very little about what that regulatory DNA landscape actually does. However, we do know that it is of great importance. This is demonstrated if nothing else by comparisons with other species, such as primates or mice where more than 95 per cent of the structural-protein part is conserved or identical and yet we are so different."
More than 90 per cent of intellectual disabilities for which the cause has been identified to date are attributable to alterations in the structural, ‘protein coding’ parts of our genes. In this case, on the other hand, it was in the extensive regulatory system that the problem was to be found. Professor Gecz believes that the link he and his team have found to the regulation of gene expression in this case will colour the landscape of future research into the causes of intellectual disabilities.
"About 50 per cent of intellectual disability currently goes undiagnosed," he remarked. "We believe that as a result of our work many will start looking at the 'controlling' part of our genomes and investigate that DNA, which has for many years been referred to as junk DNA.
"It is significantly harder to look for problems in this part of DNA as it is not that obvious what is disease-relevant and what is not, but at least now we have a good precedent on how to tackle it and how to deal with it when we find it."