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US researchers provide furtherevidence that variants in GRM3, thegene for a metabotropic glutamatereceptor, can increase the risk ofschizophrenia. In addition, by lookingat neurobiological traits (so-calledintermediate phenotypes) related toschizophrenia risk and glutamateneurotransmission, Michael Egan, DanWeinberger (National Institute ofMental Health, Bethesda, MD, USA),and colleagues provide the first cluesabout the molecular pathway betweenGRM3 genotype and increasedschizophrenia risk.

Schizophrenia is a largely geneticdisorder, involving many genes, each ofwhich has a weak effect on risk. “Thepolygenic nature of schizophreniamakes it hard to identify these genes”,explains Egan, “large sample sizes areneeded and to date most studies havebeen underpowered for detecting geneswith weak effect.”

One candidate gene is GRM3,which encodes a receptor that

modulates synaptic glutamate.Glutamate neurotransmission has longbeen implicated in schizophrenia, notesEgan. “For example, the drug PCP[phencyclidine], which producespsychotic symptoms when ingested,seems to work by blocking a glutamatereceptor.” Some of PCP’s adverseeffects can be blocked by agonists ofGRM2 and GRM3.

In 2000, a genome-wide linkageanalysis of schizophrenia in Finlandreported a linkage between the genomicregion around GRM3 and schizo-phrenia. Then, in 2002 and 2003, twoassociation studies homed in on GRM3itself. To strengthen the case for GRM3being involved in schizophrenia, Eganand co-workers have now looked forconvergent biological and molecularevidence to link a GRM3 variant to thepathophysiology of schizophrenia.

The researchers identified a single-nucleotide polymorphism of GRM3 inintron 2 that is associated withincreased schizophrenia risk and

showed that this variant is associatedwith cognitive impairments generallyseen in schizophrenia. “We then goback a step and use functional MRI toshow this allele is associated with phys-iological abnormalities in the prefrontalcortex and hippocampus”, says Egan.Another step back indicates that theallele also affects prefrontal glutamateneurotransmission (Proc Natl Acad SciUSA 2004; 101: 12604–09).

“These findings further highlightglutamate’s involvement in theaetiology of schizophrenia”, commentsJesper Ekelund (Columbia University,NY, USA), lead author of the Finnishlinkage analysis. “More importantly,they suggest a possible link between thegenetic findings and the clinicalphenotype of schizophrenia. Only byunderstanding the molecular pathwaysfrom gene to disorder will we be able todevelop treatment and prevention forschizophrenia in a more targeted way”,he concludes.Jane Bradbury

Schizophrenia molecular pathway emerges

Joubert syndrome may provide clues about human evolutionAHI1 is the first gene to be implicatedin Joubert syndrome (JS), a rare mal-formation of the cerebellar vermis andbrainstem with abnormalities of axoncrossing. “While JS is prettydistinctive clinically it has been verydifficult to understand genetically”,researcher Chris Walsh (HarvardMedical School, MA, USA) told TheLancet Neurology.

As well as enabling a greaterunderstanding of the disease andopening up the potential for geneticcounselling and prenatal testing, thisfinding will help advance researchinto the mechanisms of axon crossingin the brain or “decussation”.

How axonal growth cones cross thehuge relative distances from the cortexto their cell bodies in the brainstem toform the complex patterns of decus-sation has long eluded neuroscience.“AHI1 is a new gene never beforeimplicated in the process and linkshuman disease to basic studies inexperimental animals”, says Walsh.

The researchers investigated thegenes in a locus on chromosome 6q inthree families from Saudi Arabia withautosomal recessive JS. In each family,they identified different deleteriousmutations in a novel gene calledAHI1. (Nat Genet 2004; 36: 1008–13).

Although renal abnormalities canoccur in some forms of JS, theindividuals studied did not have renalsymptoms, which suggests that AHI1is involved in this particular type ofJS. “In the last few years we havebecome aware that in JS-relateddisorder, clinical heterogeneity goeswith genetic heterogeneity”, explainsEnrico Bertini (Bambino Gesu’Research Children’s Hospital, Rome,Italy). A pure cerebellar type is linkedto chromosome 9q, whereas JS withrenal involvement has been linked toa locus on chromosome 11. Leadauthor of the paper, Russ Ferland,says that the identification of AHI1will further our understanding of therole of AHI1 in JS as well as help in the

establishing of other subclassificationsof the disorder.

Ferland and colleagues also lookedat the expression of Ahi1 in mice totry to better understand its role:“since individuals with Joubertsyndrome lack a cerebellar vermis andAhi1 expression occurs very early inmouse cerebellar development, thenAHI1 may have an important role inthe formation or patterning of thecerebellar vermis”. Another clueabout the function of AHI1 comesfrom sequence comparisons of thehuman gene with that of mice andnon-human primates. The changes inthe gene suggests that there has beenselection pressure on the gene in thehuman lineage. Given this pressureand the known defects of axonalcrossing in JS, Ferland suggests thatevolution in AHI1 may have beenimportant in the development ofhuman beings’ unique motorcapabilities, such as bipedalism.Peter Hayward

Neurology Vol 3 October 2004 http://neurology.thelancet.com