Meckel-Gruber syndrome research
Professor Michael Eccles
A Centre for Reproduction and Genomics research team has made a big step towards a treatment for a serious form of kidney disease, with early-stage preclinical studies now generating results.
Meckel-Gruber syndrome is a rare but catastrophic form of Polycystic Kidney Disease that affects multiple organs and often leads to an early death, particularly in childhood.
Discoveries on the genetics of the disease could not only help develop knowledge of the causes and find a way to help those affected, but may also shed some light on a range of related diseases, says research leader Professor Michael Eccles.
“There are a lot of really interesting aspects to this Polycystic Kidney Disease syndrome. Genetically it’s becoming a real gold mine for what it will tell us in the long run about the biology of the kidney.”
The project was originally initiated ten years ago, when it was discovered that two unrelated New Zealand sheep flocks are the only animals in the world (aside from some rare strains of mice) known to be naturally affected by the disease. This means that a suitable large animal model is easily accessible for studies right here in Otago, with the added assistance of a team of experts at AgResearch Invermay.
With the help of John McEwan, the project team has access to AgResearch’s extensive library of sheep genome resources and technologies such as the SNP50 sequencing chip, says Professor Eccles.
“We had a bit of breakthrough when our lab teams began screening on SNP50. It helped to home in on a few specific areas in the genome, and we identified some very likely candidate genes. During the DNA sequencing to find potential mutations, we found two possible mutations within the same exon that both looked although they could affect the function of the gene.”
Looking in more detail, the objective is now to prove that the mutations found can adversely affect the primary cilium, the cell structure that is responsible for signalling pathways between organs.
It is possible that these mutations could also be responsible for a suite of similar syndromes, such as nephronophthisis and Joubert syndrome, which appear similar but are less severe and not as frequently fatal. Developing a better understanding of Meckel-Gruber could therefore help a significant number of people worldwide affected by various diseases of the kidney, and working out a way to do this is already in progress. Professor Eccles’ team is currently trialling a possible treatment, rapamycin, which is looking promising. Although affected lambs were stillborn, they exhibited a slightly improved kidney condition and also appeared to show an improvement of symptoms in the liver, which is often affected in conjunction with the kidneys.
Testing is also being undertaken using the zebrafish, an animal model of universal value due to the way it can be easily manipulated, and which is readily available at the university zebrafish facility. Replicating results on another model species will help demonstrate the accuracy of the genetic discovery.
Next generation DNA sequencing will also continue in order to check the sequence variation within the gene locus and show that the mutations that have been identified are unique to the affected NZ sheep.
