Genetic mutation underlies mental retardation

Mental retardation was once only spoken of in hushed voices, usually suffused with pity and, in some cases, shame. Often, mentally retarded children were thought of as their parents' divine punishment.

Thankfully, times have changed. Mental retardation is now viewed as a developmental disease, not as a manifestation of the gods' wrath.

While several types of mental retardation appear to have environmental causes - for example, exposure to mercury - some of the more prevalent kinds, like Down syndrome, are caused by an abnormal genetic make-up.

Recently Hopkins researchers, in conjunction with colleagues in the U.K., China and Australia, identified five different mutations of the same gene that appear to underlie one hereditary form of mental retardation, called X-linked mental retardation.

As its name suggests, X-linked mental retardation (XLMR) is related to the X chromosome. The X chromosome is one of two sex chromosomes, the other being Y. Males possess one of each type, while females possess two Xs. Thus, every male gets his X chromosome from his mother.

If a boy has a defective X chromosome from his mother, he doesn't have one from his father to cancel out its negative effects. Indeed, one in 600 males has the disorder, a much higher rate than is found in females.

Because other cases of gene-linked mental retardation are generally sporadic within families and not caused by mutations on a sex chromosome, researchers have had a hard time pinning down exactly which genes are involved.

XLMR, on the other hand, is passed from generation to generation in a predictable way and on a particular chromosome. This allowed researchers to focus on a single location - the X chromosome - in their search for genetic causes.

Indeed, before the Hopkins study, 59 relatively common XLMR genes had already been identified. This, however, is only about half the number of genes researchers suspect contribute to XLMR.

The remaining 100 genes are probably very rare, affecting only a handful of families and, even then, only a few individuals.

Nonetheless, the Hopkins team appears to have found one.

The gene, GRIA3, encodes AMPA receptors, some of the most important proteins in the human brain. AMPA receptors, found primarily at the junction between nerve cells, bind glutamate, the nervous system's most common neurotransmitter.

When bound, glutamate - read by the cell as an excitatory signal - causes an AMPA receptor's shape to change, permitting the influx of millions of positively charged ions. This flow of electric charge eventually becomes self-propagating and gets transmitted to neighboring neurons.

In essence, AMPA receptors produce a signal that can be read by every cell in the nervous system. A veritable mountain of new research has shown that changes in the interaction between glutamate and AMPA receptors is the basis for learning and memory on the cellular level.

In the present study, the fortuitous finding that one subject had a ten-fold reduction in the expression of GRIA3 led the researchers to collect DNA samples from 400 unrelated males, all with XLMR. In one subject, the entire GRIA3 gene was deleted. In four other individuals, the team identified four distinct changes to the gene's code.

Hypothesizing that each of these variants caused a deformity in the AMPA receptor, the team inserted the mutated DNA into a group of genetically "blank" kidney cells derived from human embryos. One mutation produced 78 percent less AMPA receptor than normal, while two others rendered the receptor unable to let ions pass through.

These deficits, the researchers say, are due to the location of each mutation along the string of amino acids - the building blocks of a protein - that form the AMPA receptor. One mutation, for example, probably causes misshaping of the area where glutamate is thought to bind; another likely deforms the channel through which the positively charged ions pass.

To bolster their findings, the team screened a group of 500 normal males to see if they possessed a deletion or any of the four mutations in GRIA3. None of them did. Nonetheless, the researchers cautioned that on a cellular level, defective AMPA receptors may not lead directly to mental retardation.

Instead, a lack of functional AMPA receptors could indirectly change the how the brain gets wired during development. In future studies, the team expects to use animal models of the AMPA mutations to settle the question.