Study probes into how gene mutation causes autism, intellectual disability

Northwestern Medicine researchers have discovered why a specific genetic mutation causes intellectual disability and autism spectrum disorder in children.

They found genetic mutations in human patients in a gene called Usp9x result in the brain growing fewer synapses. That’s because Usp9x protects another protein called ankyrin-G, whose role is to grow and stabilize synapses. The developing brain needs to build lots of synapses between neurons so cells can communicate while the brain grows, and to learn.

When Usp9x is mutated, it can’t stabilize the synapse-enhancing ankyrin-G. Thus, the would-be enhancer protein degrades and destabilizes, resulting in fewer synapses in the brain. Individuals with this mutation have developmental delay, difficulty learning, increased anxiety and hyperactivity.

In addition to ankyrin-G, Usp9x also protects several other important synapse-enhancing proteins, which when mutated also cause intellectual disability and autism. Usp9x is a master-stabilizer of many key proteins essential for brain development and learning.

It is notable that severe mutations in ankyrin-G are also known to cause intellectual disability and autism. Or, if a person inherits a less severe form of the mutation in ankyrin-G, their synapses develop relatively normally in childhood. But during adolescence when there is a big turnover of synapses as the brain matures, more of these vital neuron connectors are lost than normal. The result can be schizophrenia and bipolar disease.

Interestingly, Usp9x and related proteins are also involved in cancer and have been of interest to the pharmaceutical industry. Hence, some candidates from the cancer drug development process could potentially be used to target Usp9x to treat some forms of intellectual disability, autism, schizophrenia and bipolar disorder.

The study was published on Thursday in Neuron.

Northwestern Medicine is the collaboration between Northwestern Memorial Healthcare and Northwestern University Feinberg School of Medicine, which includes research, teaching and patient care.