Many faces of the same gene
Unstable mutations. Global deregulation. The terms could be those used by the pundits seeking to understand the state of financial collapse currently preoccupying the world.
Unfortunately economics is not the only system prone to misadventure. Within the human genome, faults in the system that manages the way our genes are passed on from generation to generation also preoccupy researchers.
La Trobe geneticist and neurologist Dr Danuta Loesch has been studying families affected by one of those faulty genes for more than twenty years – and these are terms she uses to describe their impact on carriers.
The mutation in this gene is unstable across generations, she says. At its very worst, it causes Fragile X Syndrome which presents with severe intellectual disability and behavioural problems such as autism – hence its name: the Fragile X Mental Retardation (FMR1) gene.
These serious problems occur, says Dr Loesch, because the gene is shut down and does not produce protein essential for brain development.
‘This genetic change is called full mutation, and males are at a greater risk of severe problems than females, because the gene is X-linked and therefore the second X-chromosome in females can balance the damage.’
The instability is in the number of CGG repeats – three nucleotides that are the building blocks of DNA – situated in the ‘regulatory’ part of the gene.
‘Their number can gradually increase across many generations, from the normal range (7-40 repeats), through the intermediate “grey zone” range, to the pre-mutation range (55-200 repeats),’ she says. ‘Premutation can expand to the full mutation in one generation if transmitted through the mothers. These three zones appear to be linked to the severity of symptoms.’
A unique aspect of Dr Loesch’s study is that she is looking at the smallest expansions of CGG and their effects on people’s health.
In a ten year study funded by the US National Institutes of Health, conducted in collaboration with Professor Randi Hagerman and her team from the University of California at Davis, Dr Loesch has been studying people with genes in between these two extremes which represent a less serious form of the mutation.
Until recently, scientists believed that these forms had no clinical effects, and they were recognised solely because, if passed on, could predispose children of the carriers to full mutation. But Professor Hagerman and Dr Loesch contradicted this belief. Their early findings showed that these small expansions were associated with some behavioural or learning problems.
Then in 2000, Dr Loesch received a call from Professor Hagerman. ‘She called and asked if I saw many people with Parkinson’s Disease in my Fragile X families, because she had come across a few in hers. I said yes, amongst grandparents of children with Fragile X Syndrome. But Parkinson’s disease is very common in the general population, so I couldn’t believe there was a connection. The evidence was still anecdotal.’
That led to a full-scale study which included large samples of pre-mutation male carriers recruited both in Australia and the US. The researchers did neurological examinations and came up with some surprising results.
They found that, in both Australian and US samples, male carriers over the age of fifty were prone to develop tremor-imbalance syndrome associated with cognitive decline. The frequency ranged from 38 per cent for carriers aged 60 -69 to 75 per cent at the age of 80 and over.
‘This was a very substantial finding,’ Dr Loesch says.
Then other researchers investigating female pre-mutation carriers found a 20 per cent increase in the risk of ovarian failure. These women were going into menopause in their late thirties and were turning up at IVF clinics.
‘This is a big issue,’ Dr Loesch explains. ‘It’s a unique situation because you usually have one type of disorder in people carrying a standard type of mutation. Here you have many faces of the same gene, some mutations causing major developmental abnormalities and other late-onset disorders through different mechanisms.’
‘Our research has shown that, in premutation carriers, the FMR1 gene is not shut down; quite the opposite, it is overactive and thus produces a higher quantity of gene transcript-messenger RNA. It was therefore concluded that elevated levels of this RNA may be toxic, causing premature death of brain cells, which was soon confirmed by studies in animals.’
Now, the researchers suspect that even those people carrying repeats in the 41-54 (grey zone) range might have some clinical symptoms similar to those seen in pre-mutation carriers. This is because, in her latest study (published in the Journal of Medical Genetics in 2007), Dr Loesch showed that these carriers also produce excessive amounts of messenger RNA.
‘This category is so important because one in thirty or forty people from the general population is a carrier in the “grey” area. It’s very common, and therefore even small clinical effects are borne by a great number of individuals.’
Dr Loesch is not in the business of scaring carriers of the mutation. Her life’s work aims to understand the mechanisms that drive its expression. ‘We are not doing the work to frighten people or label them, but to make estimates of the risks. They may be lower than people think,’ she says.
‘Further, our current study conducted in collaboration with the Murdoch Children’s Research Institute of the Royal Children’s Hospital in Melbourne, is trying to find out what is involved in that RNA toxicity. Our first results suggest that elevated levels of RNA with small expansions of the three nucleotide CGG repeats may trigger deregulation of many other genes – which leads to clinical abnormality.
‘Once this is confirmed,’ says Dr Loesch, ‘it opens real prospects for treatment and prevention.’