Master of autism

How a CPEB4 isoform imbalance could be the key to modeling polygenic autism

The discovery of a master regulator of autism risk genes has yielded the first mouse model of the form of the condition that accounts for about 90% of patients, and could spark a new way of thinking about how to model polygenic diseases.

Like many neurological conditions, the vast majority of autism cases are idiopathic, not driven by a single mutation but by the complex interplay of small genetic risk factors as well as environmental influences.

Genome-wide association studies (GWAS) have linked autism to polymorphisms in over 1,000 genes, according to the Simons Foundation Autism Research Initiative (SFARI) database.

Yet virtually all translational work in neurological diseases, from autism spectrum disorders (ASDs) to Alzheimer’s disease, is done on mouse models that mimic rare monogenic mutations, calling into question the relevance of the findings to the broader patient population. The entire field of neurology stands to benefit from fresh ideas about how to model polygenic disease.

Part of the hold-up has been that individual SNPs typically convey a small amount of disease risk, and creating mice that harbor large numbers of SNPs is impractical. Moreover, some human polymorphisms don’t exist in mice.

A Nature paper published this month has broken that barrier by identifying and exploiting a single gene that controls expression of a large number of autism risk genes in patients. The gene encodes the RNA-binding protein and translational regulator CPEB4.

Study leader José Lucas, a research professor at the Carlos III Health Institute in Madrid, told BioCentury the group’s CPEB4-based mouse model has both construct and face validity, meaning it mirrors both the molecular etiology and the symptoms of the human disease. He thinks

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