Unpicking the seam of a disease gene: Who matters, Mum or Dad?

Scientists studying Rett Syndrome, a serious genetic brain disorder, have found that inheriting the faulty gene from the father, rather than the mother, can influence the severity of the disease. These findings, from teams at the Children’s Medical Research Institute and Western Sydney Genetics program at The Children’s Hospital at Westmead, may pave the way to improving genetic screening and potential treatment programs.

Rett Syndrome is the second most common cause of severed intellectual disability in girls after Down Syndrome, affecting one in 10,000 births. It is a devastating condition characterized by progressive loss of speech and movement and the development of intellectual disability at a very young age and as the child grows up.

Recent work by this team of clinicians and scientists has been published in Human Molecular Genetics and the American Journal of Human Genetics.  The research, led by Dr Patrick Tam and Prof John Christodoulou, has revealed that inheriting the faulty gene, known as MECP2, from either the dad or the mum has a significant impact on how severe the disease might become. This finding, which is now shown more clearly in an animal model study, gives weight to the theory of genetic imprinting – that the role of a gene and therefore health and characteristics of a child, depends on whether the gene is inherited from the mother or father.

By studying Rett Syndrome in a mouse, post-doctoral scientist Greg Pelka, discovered that the MECP2 gene is critically important for movement, balance and learning; the very skills that are lost in girls affected by Rett Syndrome. Dr Pelka says, “This finding has provided the best indication to date about the role of the MECP2 gene in learning and cognitive ability.”

In related work, The Children’s Hospital at Westmead and CMRI teams, in collaboration with researchers in Adelaide and the UK, have discovered a second gene, CDKL5, which can cause features similar to Rett Syndrome and may also cause epilepsy and autism.

Professor Christodoulou explains, “Like MECP2, little is known about how CDKL5 affects brain development and function, so these discoveries have opened up great opportunities to begin to unravel these complex processes.”

Scientists hope these findings will lead to novel insights into intellectual disability, epilepsy and autism and with more research, will pave the way to the development of targeted new therapies.

The continuing work on Rett Syndrome has recently received support from Ian Thorpe’s Fountain for youth.