Point mutation in fragile X gene reveals separable functions in brain

A new paper in PNAS from geneticist Steve Warren and colleagues illustrates the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]

Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.

However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warren’s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X protein’s multifaceted functions.

Emory MD/PhD student Leila Myrick is the first author of the PNAS paper, and the Emory team collaborated with Vitaly Klyachko’s lab at Washington University, St. Louis.

The fragile X protein is known to bind RNA and regulate protein production in neurons, but a mutation identified in one patient (called R138Q) leaves that function intact, the authors report. The mutation instead interferes with another function of the fragile X protein, where it interacts directly with ion channels.

The authors write that the boy affected by this mutation has intellectual disability and intractable seizures, but no other features of fragile X syndrome such as changes in facial features or large testes. Two other point mutations in fragile X protein have been previously identified in patients, but those mutations disrupted the RNA-regulatory functions, and the affected patients’ symptoms closely resembled “classic” fragile X syndrome.

Posted on by Quinn Eastman in Neuro Leave a comment

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Quinn Eastman

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