BioWorld International Correspondent

LONDON - Identification of a gene responsible for some cases of inherited severe mental retardation has allowed unexpected insights into one of the causes of this common condition.

The gene encodes a protein that is found in presynaptic vesicles in adult human brains, and might be involved in synaptic transmission of nerve impulses. Researchers predict that further investigation of the physiological pathways involved will help them understand how learning and memory develop normally.

Laurence Colleaux, a molecular biologist at the H pital Necker in Paris, told BioWorld International, "What we have found is a totally novel pathophysiological basis for mental retardation in humans."

Colleaux, together with her colleagues at INSERM in Paris and collaborators elsewhere in France and at the University of Zurich in Switzerland report their discovery in a paper in Nov. 29. 2002, issue of Science. The paper is titled "Truncating Neurotrypsin Mutation in Autosomal Recessive Nonsyndromic Mental Retardation."

Colleaux, whose work has been funded by the charity Fondation de France, said she was studying the genetics of severe mental retardation because it was the most common handicap, affecting up to 0.8 percent of the population. About half of all cases have a genetic cause. Most of these cases are sporadic, but about 10 percent are familial.

An estimated 300 genes are thought to play a role in mental retardation, and only 11 genes responsible for mental retardation not associated with named syndromes (known as nonsyndromic mental retardation) are known. So far, all characterized genes have been on the X chromosome, rather than on one of the autosomes.

"I was interested in identifying genes responsible for cases of nonsyndromic mental retardation in which there are cognitive defects but no other abnormality because I think these will supply a great deal of information about the normal development of cognitive function and how learning and memory develop," Colleaux said.

The search for such genes has been difficult because large affected families are rare. Colleaux and her colleagues therefore tried to track down some of the genes by studying consanguineous families (families in which first cousins have married) using a technique known as homozygosity mapping. The process involves looking for regions of the genome common to all affected individuals, in which the inherited genes are the same on both paternal and maternal strands of the chromosomes.

The technique allowed the team to identify a single region of shared homozygosity on chromosome 4 that had been inherited by four affected siblings (but not by their four healthy siblings) born to first-cousin Algerian parents.

Further studies showed that there were 29 known genes in this region. Out of these, the researchers decided to focus on the gene encoding neurotrypsin, a member of the trypsin-like serine proteases, partly because the Swiss authors of their paper had already shown that this was expressed in the brain.

Their hunch was correct. They found that all the affected children were homozygous for a mutation in the gene, which had the effect of prematurely stopping manufacture of its protein. The parents, too, were heterozygous for the mutation. A study of 200 controls showed that none had the mutation.

Searching for the same mutation in 23 mentally retarded children belonging to 17 other inbred families affected by sporadic mental retardation, the team found the same mutation in a child born to first-cousin Algerian parents. The two families with the mutation were not related, but both came from the same area of Eastern Algeria.

A battery of experiments by the team, looking at the expression of neurotrypsin in fetal and adult human brain, showed that the protein is mainly found in the cerebral cortex and the motor nuclei of the brain stem, and is concentrated in vesicles adjacent to the presynaptic membranes of synapses.

Colleaux said: "We hypothesize that neurotrypsin is secreted from the presynaptic end of the neuron, and that it activates a receptor in the synaptic cleft, presumably by cleaving it, and so allows the signaling pathway to continue. This finding is very important because synaptic proteolysis has never before been shown to be involved in mental retardation in humans. If we can understand this process better, it will tell us a great deal about the normal development of cognitive function."

Neurotrypsin, she said, belongs to a large family of proteins.

"It is possible that all members of this family, when mutated, could potentially cause mental retardation, and we are currently testing this hypothesis," she said. The group also is looking for other families affected by mutations in the neurotrypsin gene.