Gypsy Study Unravels a Novel Ataxia Gene

August 21st, 2012

A Western Australian study on an isolated population of Gypsies, known as Bowlmakers, has unlocked clues about a serious developmental disease, congenital cerebellar ataxia. The discovery of an important genetic mutation is likely to inspire other scientific work around the world.

Western Australian Institute for Medical Research (WAIMR) scientists, Professor Luba Kalaydjieva and Dr Dimitar Azmanov worked collaboratively with other Australian and European researchers to discover mutations within a gene which has never been linked to this form of heredity ataxia in humans.

Ataxias are a large group of neurodegenerative disorders which affect the ability to maintain balance, and learn and maintain motor skills. While many genes have already been implicated in hereditary ataxias, understanding their molecular basis is far from complete. New knowledge will help the understanding of normal brain development and function and the mechanisms of degeneration.

"Gypsies are a founder population," explained Professor Kalaydjieva. "They are derived from a small number of ancestors, and have remained relatively isolated from surrounding populations. The Bowlmakers, known for their wooden handicrafts such as bowls and spoons, were an ideal group to study because they are a younger sub-isolate, showing limited genetic diversity.

"We studied a novel form of ataxia in 3 families in this ethnic group. Clinical and brain-imaging investigations were done in Bulgaria, in collaboration with radiologists from SCGH and PMH, and were followed-up by genetic studies at WAIMR and the Walter and Eliza Hall Institute (WEHI), Melbourne."

"Signs of ataxia were detected in early infancy when motor skills like crawling and rolling over did not develop. The affected individuals presented with global developmental delay, ataxia, and intellectual deficit. MRI scans showed signs of degeneration of the cerebellum, which is part of the brain controlling motor and learning skills. Overall, the life expectancy is not decreased, but the quality of life is severely affected."

"The parents of the affected individuals did not present with any clinical symptoms of the ataxia, suggesting recessive inheritance" explained Dr Dimitar Azmanov. "Our genetic studies showed unique changes in the gene encoding metabotropic glutamate receptor 1 (GRM1). This receptor is important for the normal development of the cerbellar cortex. The mutations inherited by all affected individuals from their unaffected carrier parents dramatically altered the structure of the GRM1 receptor."

Prof Kalaydjieva indicated that the exact pathogenetic mechanisms leading to the clinical manifestations and cerebellar degeneration are yet to be explained and that this opens novel research avenues for the wider scientific community. "It also remains to be seen if other ataxia patients around the world carry mutations in GRM1."

Dr Azmanov said that the research, from the recruitment of the families to the final gene identification and characterisation of the mutations only took 6 months thanks to the highly sophisticated technology of whole-exome next generation sequencing. "In previous years the same research would have taken up to 10 times longer (or more) and would have required larger and/or many more families with the same phenotype.It's now possible to look at very rare diseases in small families."

Professor Luba Kalaydjieva, who has been working on the genetics of the Roma people for the past 20 years, has recently retired from WAIMR. Her studies are the focus of ongoing research into a number of hereditary neurologic disorders. Dr Azmanov has been actively involved in genetic studies in the Gypsy founder population for the last five years and his work has been supported by a National Health and Medical Research Council Training Fellowship (634551). The current study has been published online today in the prestigious American Journal of Human Genetics.

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