Autism Advance: Mutated genes disrupt nerve cell proteins

A French research team has identified two mutated genes that appear to cause the neurological disorder known as autism. The little-studied genes both normally yield proteins that nerve cells use to form communication channels.

“These are the first genes convincingly linked to autism,” says team member Thomas Bourgeron of the Pasteur Institute in Paris.

Other researchers find the evidence compelling, if not quite conclusive. “These are really good candidates” for autism genes, says Edwin Cook of the University of Chicago.

Autism is a puzzling disorder in which individuals have trouble interacting with other people or the environment. If the new findings lead to an understanding of what goes awry in autism, researchers might find a new way to treat the disorder and gain insight into the normal function of the human brain, says Bourgeron.

The newly implicated genes encode proteins called neuroligins, which appear on nerve cells at the specialized junctions known as synapses. It’s at a synapse that one nerve cell releases chemicals to signal an adjoining nerve cell. Researchers have found that neuroligins help create a synapse by physically connecting two nerve cells at that location.

In an upcoming Nature Genetics, Bourgeron and his colleagues report finding mutations in the two known neuroligin genes on the X chromosome. The researchers studied two Swedish families, each having two boys affected by autism or Asperger syndrome, a disorder that shares some features with autism. In one family, the mutation disrupts a neuroligin gene so severely that the protein produced is truncated. In the other family, the mutation is subtler, altering a single amino acid on a neuroligin protein.

The mutations in both cases appear to have originated in the mother and then been passed on to sons. Since women have two X chromosomes, the mothers had a backup copy of a normal neuroligin gene that presumably protected them from developing autism. Their impaired sons, however, inherited the single X chromosome with the mutated gene. The Y chromosome each boy inherits from his father carries a neuroligin gene, but it doesn’t appear to compensate for a defective neuroligin gene on the X.

Autism appears in four times as many men as women, so scientists have long suspected that the X chromosome contains relevant genes. It’s not clear, however, whether the new findings account for this sex bias. “So far as we can tell, these mutations are rare events and thus whilst explaining why some vulnerable males have autism, they are not contributing to the general liability to autism,” says David Skuse of University College London.

Few scientists have investigated neuroligins, says Thomas Sudhoff of the University of Texas Southwestern Medical Center in Dallas, who was part of the group that in 1995 identified the first neuroligin gene. The newfound connection to autism is “the first time that a protein associated with synaptic cell adhesion is implicated in a disease,” he says.

Some scientists suspect that the other three known neuroligin genes may also be involved in autism. Last year, a study of Finnish families with autism implicated the chromosome 3 region where a neuroligin gene dwells. Leena Peltonen of the National Public Health Institute in Finland and the University of California, Los Angeles, a coauthor on that study, tells Science News that her group is examining those families’ copies of the chromosome 3 neuroligin gene. The new report “is a highly encouraging finding and will definitely focus the interest of autism researchers on this gene family,” she says.

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