Neurobiology of RAI1, the causal gene for Smith-Magenis syndrome

In most cases of autism, the cause is unknown. However, a number of rare syndromes caused by known genetic abnormalities include features of autism, and understanding the mechanism by which these syndromic forms develop may provide insight into autism more generally.

Liqun Luo and his colleagues at the Howard Hughes Medical Institute and Stanford University hope to shed light on autism by studying a rare neurodevelopmental disorder called Smith-Magenis syndrome (SMS). In most cases, SMS is caused by the loss of a segment of chromosome 17 that includes many genes. However, some people with SMS have specific mutations in a single gene, called RAI1, in this chromosomal region.

Most SMS symptoms — which include cognitive delay, repetitive and self‐injurious behaviors, circadian rhythm and sleep abnormalities and other features associated with autism — are caused by loss of function of one copy of RAI1. Investigators previously generated mice that are missing one copy of RAI1 and found that they have several characteristics that resemble symptoms of SMS¹. To gain further insight into the function of RAI1 and how its loss may result in SMS, Luo’s team generated mice in which one or both copies RAI1 were removed from different populations of cells in the brain.

They found that losing both copies of RAI1 in all neurons and glia causes obesity, motor dysfunction, learning and memory deficits, and death in early- to mid‐adulthood in the mice. Removing RAI1 only from neurons that manufacture gamma-aminobutyric acid, a particular inhibitory neurotransmitter, recapitulated the learning phenotype. This suggests that RAI1 function in these cells is required for normal cognitive function. Removing RAI1 from excitatory neurons in the forebrain or from glial cells in the brain does not produce any behavioral phenotypes that could be detected by the team’s assays.