Learning about learning disability 16/11/04. By Giles Newton Linking genes to learning difficulties.

A child's intellectual development is a fascinating and delightful process. Soaking up experiences like a sponge, the child learns, becomes able to solve problems, think abstractly, make sense of the world, and so on.

For children with learning disabilities, development may be slower and they never attain the same learning abilities. Although the causes are often clear, in about 40 per cent of cases the underlying cause – whether environmental, genetic or both – remains mysterious.

Unknown genetic factors are the focus of Dr Lucy Raymond's research at the University of Cambridge. In 2001 she established the Genetics of Learning Disability (GOLD) study, and has collected samples from more than 400 affected families from around the world.

As affected males outnumber females, Dr Raymond's focus is on the X chromosome (unlike females, males have only one X chromosome, and a single mutation can knock out the function of a gene completely). Indeed, the most common single gene cause of learning disorder is fragile X, which may account for about 3 per cent of learning disorders in males.

Background: Fragile-X syndrome

"It's clear that there are many genes involved in learning disability," says Dr Raymond, "and there is good evidence that as many as 70 genes on the X chromosome may be responsible. There are more than 700 genes on the X chromosome, any of which could be the culprit. For each gene that has been identified so far, the numbers of people affected are few as the mutations are rare. We therefore need to look at lots of genes, in a high-throughput manner, and as each mutation is rare, we need very accurate detection. A single base-pair change in the DNA can have a big effect."

Dr Raymond has therefore teamed up with Mike Stratton's group, the Cancer Genome Project at the Wellcome Trust Sanger Institute, who are searching for the genetic mutations that underlie cancer.

Feature: The origins of the Cancer Genome Project

"We share an interest in the technology although the questions are different," she says. The idea is to use DNA sequencing to examine the base pairs in large numbers of X chromosome genes, and to compare them to the reference human genome sequence – a Herculean task.

Linking genes to learning

Proof that the strategy works comes from a family in which four males with moderate to severe learning disability were found to have a mutation in a gene called DLG3, as did the unaffected carrier females who had passed on the mutation. Dr Raymond then looked at the DLG3 gene in more than 300 other affected families, and found that three more families had mutations in the same gene, but each family’s mutation was different.

"For one branch of the first family, the finding had particular significance," says Dr Raymond. "Three daughters had held off reproductive decisions, because of the family history of learning disability. We found that their mother was not a carrier, so they did not have the mutation."

The gene itself is also of interest, for the protein it produces, called SAP102, is found at the junctions between nerves and binds to a molecule crucial to learning and memory, the NMDA receptor. And it is closely related to a gene (PSD95) that Professor Seth Grant’s team had inactivated in mice a few years previously, resulting in mice with severe learning deficits.

Feature: Genes and cognition

"We're in a very interesting situation," says Dr Raymond. "We find a new gene that has a direct impact on several families, in particular because it gives a reason for the learning disability. But it is also very important to the idea that intellectual disability can be due to the incorrect function of NMDA receptors. This is the first concrete example in humans that shows the hypothesis to be true."

Further reading

Tarpey P et al. Mutations in the DLG3 gene cause non-syndromic X-linked mental retardation. Am J Hum Genet 2004 75:318-324. Abstract ; Full text