A PNAS paper published MondayÂ demonstrates the kinds of insights that can be gleaned from a large scale sequencing project examining the fragile X gene.
Most children (boys, usually) who have fragile X syndrome have a particular mutation. An expanded â€œtriplet repeatâ€ stretch of DNA, which is outside the protein-coding region of the gene, puts the entire gene to sleep.
At Emory,Â geneticist Steve Warren, cell biologist Gary Bassell and colleagues have been identifying less common changesÂ in the fragile X gene by looking in boys who are developmentally delayed, but donâ€™t have the triplet repeat expansion. The first author of the paper is former postdoc Joshua Suhl, now at Booz Allen Hamilton in Massachusetts.
The authors describe two half-brothers who have the same genetic variant, which changes how production of the FMRP protein is regulated.Â These examples show that the fragile X gene is so central to how neurons function that several kinds of geneticÂ glitches in it can make this finely tuned machine break down.
â€œThis is a hot area and not much is known about it,â€ Warren says.
By binding RNA, the FMRP protein controls protein synthesis for many genes in neurons, but this is only part of the story. It is not enough to simply haveÂ enough functional FMRP protein around when the neuron is in a resting state. FMRP, anÂ important regulator, needs to be regulated.
Whatâ€™s disrupted in the two boys is production of more FMRP protein in response to signals from glutamate receptors. A one-letter mutation changes an interaction between the fragile X messenger RNA and the RNA-binding protein HuR, the authors show.
Recall that glutamate is a major excitatory neurotransmitter, and glutamate signals degrade pre-existing FMRP. Then newly synthesized FMRP is supposed to reign in the resulting burst of protein synthesis. The mutations in the two boys appear to prolong and flatten outÂ this feedback loop — resulting in intellectual disability. The same mutations were foundÂ in several other boys in the same sequencing study.
Glutamate receptor blocker drugs were a major part of a clinical trial strategy for fragile X syndrome, which is now being reevaluated.
A related PNAS paper from earlier this year emphasized that the fragile X protein has two functions: one related to RNA binding and an independent function connected with ion channels. This distinction was revealed by studying a patient with a mutation that altered only the second function. The patient had intellectual disability and seizures, but not other aspects of fragile X syndrome.