Researchers have found that different mutations in a single gene can have myriad effects on a person's health, suggesting that gene therapies may need to do more than just replenish the missing or dysfunctional protein the gene is supposed to encode, according to a study published in Nature Genetics.

Patients with schizophrenia, autism, and bipolar disorder sometimes carry mutations in NRXN1 (Neurexin1). Until now, NRXN1 "had largely been studied only in mice. And, from the mouse studies, we know there are over 300 splice isoforms," said co-senoor author. "That means that this one gene makes 300 different proteins in the mouse."

The team set out to understand how NRXN1 functions in typical human neurons, and how different mutations might impact cellular function.

The team started with skin samples from several patients who had mental health diagnoses and carried mutated forms of the gene. They used these samples, as well as samples from participants without these diagnoses, to culture human induced pluripotent stem cells (hiPSCs)--cells with the ability to grow into any cell in the body.

The cells were then induced to grow into neurons. In the cells that came from patients with mutations in NRXN1, the scientists noted differences in the shape and electrical activity of the neurons as well as the rates at which they matured.

But that wasn't all. All people have two copies of the gene. If there is a mutation, it is usually only in one of those copies. The normal, unmutated gene still produces the healthy protein, but the mutated copy is unable to produce any protein, meaning the individual produces less of the protein than is necessary for normal function. The researchers figured that introducing more of the healthy protein would rescue the neurons, but this wasn't always the case.
                                                            
Some of the mutations cause the second copy of the gene to produce a separate, mutated version of the protein. The researchers found that these mutated proteins may interfere with the action of the healthy protein. The team found that even cells that could produce enough of the healthy protein that they should have functioned normally would suffer if they were also exposed to a mutant form of the protein--and different mutations led to different problems.

"Functionally, these mutant proteins seem to have a dominant negative effect," said the author. "Overexpression of a single mutant protein in healthy neurons is enough to cause them to fire irregularly."        
 
The study was small, and the gene variants the team studied are rare. In the future it will be important to tease out exactly how the variants impact function: do developmental perturbations lead to later differences in activity or vice versa? But both senior authors emphasized that the overall message is crucial for anyone hoping to use genetics to personalize medicine. 
                      
"I went into this really naively, thinking that all patients with deletions in this gene would probably show the same effect," the author said. "What we learned is that if you want to move towards precision medicine, it matters not just what genes are impacted, but how they're mutated as well." 
                
https://www.nature.com/articles/s41588-019-0539-z