Scientists funded by the National Institute of Mental Health have linked a gene that may influence human brain development with autism susceptibility. They pinpointed the candidate gene, WNT2 <http://genome.nhgri.nih.gov/chr7/cftr/Web_Fig3.pdf>, in a region of chromosome 7 suggested by several studies over the past few years. NIMH grantees Thomas Wassink
<http://iowa-mhcrc.psychiatry.uiowa.edu/new/MHCRC_Web_Page/genetics.html>, M.D., University of Iowa, and Joseph Piven
<http://www.med.unc.edu/wrkunits/1dean/admin/92299/sld038.htm>, M.D., University of North Carolina, and colleagues, report on their findings in the American Journal of Medical Genetics <http://www3.interscience.wiley.com/cgi-bin/issuetoc?ID=77002064> , available online May 17, 2001.

Rare mutations in WNT2 may "significantly increase susceptibility to autism," say the researchers, while a common variant may contribute to the disorder to a lesser degree. "While the evidence implicating this gene is good, it's not overwhelming, and must be replicated by other groups," cautioned Wassink. Affecting 1 in 500 to 1 in 2500 Americans, autism
<http://www.nimh.nih.gov/publicat/autismmenu.cfm> begins in early childhood and impairs thinking, feeling, language and the ability to relate to others.

Evidence suggests that the disorder is at least 90 percent heritable, stemming from complex interactions among 3 to 15, or more, genes. The WNT2 gene attracted the investigators' attention because of its suspect location on chromosome 7 (7q31-33); three recent genome scans had pointed to the region as likely harboring an autism gene. It is a member of a family of 16 WNT genes, a number of which are known to influence brain development. Mice bred without genes essential to the functioning of WNT genes show diminished social interaction, similar to people with autism. Also, WNT2 is located next to a broken chromosome in an individual with autism, heightening suspicion of its involvement in the disorder.

Among 135 individuals with autism screened, the researchers identified two families in which mutated variants of WNT2 were found in just one parent and in affected, but not in well, siblings. Both mutations were in coding regions of the gene. No mutated variants of WNT2 were found in 160 controls. Although they each affect only one of the gene's 1082 nucleotides, the mutations alter the amino acid composition of the WNT2 protein, and could impair the functioning of proteins and downstream biological pathways involved in brain development.

The researchers also produced evidence for the existence of a more common WNT2 variant that may be involved in more cases of autism. A nucleotide sequence variant (specifically, a single nucleotide polymorphism or SNP) in a non-coding part of the gene was found to be transmitted to autistic children more often than would be expected by chance. The SNP was also found to be associated with the group's prior evidence for linkage of 7q to autism, particularly in families with more severe language
impairment.

"Virtually all of our original 7q linkage signal had arisen from 50 families with severe language abnormalities," noted the researchers. When the researchers split those families into two groups based on the SNP variant, they found a striking separation of the linkage signal. In 24 families transmitting the associated SNP variant, the linkage signal increased from the original 2.7 to 3.7, providing strong support for linkage, while in the 26 other families, the linkage signal decreased to nearly 0.

This lopsided split in the linkage signal supports the possibility that the SNP, or an as yet undiscovered nearby polymorphism, could confer susceptibility to autism by influencing expression of WNT2. Wassink and colleagues also showed that WNT2 is expressed in the human brain's thalamus. They note that there is evidence to suggest that a circuit involving the thalamus and frontal lobes functions abnormally in autism. Since WNT2 influences brain development in animals, researchers suspect it plays a similar role in humans, but this would be difficult to demonstrate, said Wassink. The strong association between WNT2 and people with severe language impairment make the gene a strong candidate for predisposing people to this sub-type of autism, which previous studies have associated with the chromosome 7q area.

Among clues being followed up: a gene named "frizzled" that codes for a receptor for the secreted WNT proteins "is right at our linkage signal," noted Wassink. His and other groups are also looking for mutations in other genes in WNT pathways that might be involved in autism.

Also participating in the research were: Veronica Vieland, Ph.D., Jian Huang, Ph.D., Ruth Swiderski, Ph.D., Jennifer Pietila, Terry Braun, Gretel Beck, Val Sheffield, M.D., Ph.D., University of Iowa; Susan Folstein, M.D., Tufts University; Jonathan Haines, Ph.D., Vanderbilt University.

The National Institute of Mental Health (NIMH) is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

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