Copy number variations and intellectual disability

Source: University of Adelaide

Researchers led by Australian-based geneticist Dr Jozef Gecz have reported that submicroscopic copy number variations in two genes are associated with X-linked mental retardation.

The international team, including researchers from Adelaide's Women's and Children's Hospital, the Katholieke Universiteit Leuven in Belgium, the Wellcome Trust Sanger Institute in Cambridge and the University of Newcastle's Genetics of Learning Disability (GOLD) Service, found a microduplication 'hotspot' on the X chromosome containing three genes, one of which was excluded because it is not expressed in the brain and it escapes X inactivation in females.

The other two - the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 - were significantly upregulated in six unrelated families with non-syndromic X-linked mental retardation.

They suggest that the pathways of both genes contribute to normal cognitive development.

The findings are reported in the February issue of the American Journal of Human Genetics.

The researchers used array-based comparative genomic hybridisation (array-CGH) to study the X chromosomes of more than 500 families diagnosed with various forms of X-linked mental retardation.

In six of the families they discovered that a certain part of the X chromosome had been duplicated. Four of these families were from Australia. Moreover, in one of these genes, HUWE1, they identified a further three mutations in another three families, one of them from Australia.

"HUWE1 is a protein which regulates TP53, an important tumour suppressor gene," Gecz said. "One of TP53's functions is to regulate the renewal of neuronal cells in the brain. That is where we see the connection with HUWE1 and intellectual disability.

"Through this research we hope to uncover the important role that these genes and their proteins play in the normal brain development and thus learning and memory."

"Our next step is to see how frequent these mutations are among the isolated cases. Also, we will try to understand the molecular pathology of the associated disease and investigate the routes for possible future interventions and treatments."

The collaboration between the University of Adelaide and the Belgium and UK researchers started back in 2001 at a scientific meeting in Italy and gathered pace at the World Congress of Human Genetics in Brisbane in 2006.