Skip to main content
Premium Trial:

Request an Annual Quote

US National Institute of Mental Health, Fujita Health University School of Medicine, Indiana University

Premium

NIH, Japanese Team Identify Rare Mutations Linked to common Neuropsych Disorders

Researchers from the US National Institute of Mental Health and Fujita Health University School of Medicine in Toyoake, Japan have identified a rare gene mutation linked to an increased risk of developing certain common neuropsychiatric disorders such as obsessive-compulsive disorder.

A second mutation in the gene, called hSERT for human serotonin transporter gene, “suggests a genetic ‘double hit’” that may be responsible for “more severe symptoms” of OCD, the researchers found.

“In all of molecular medicine, there are few known instances where two variants within one gene have been found to alter the expression and regulation of the gene in a way that appears associated with symptoms of a disorder,” Dennis Murphy, a study co-author and researcher at the NIMH Laboratory of Clinical Science, said in a statement. “This step forward gives us a glimpse of the complications ahead in studying the genetic complexity of neuropsychiatric disorders.”

The team analyzed DNA from 170 unrelated individuals — including 30 patients each with OCD, eating disorders, and seasonal affective disorder — plus 80 controls. Scanning the hSERT gene’s coding sequence, the researchers found that substitution of the Val425 mutation for the Ile425 mutation occurred in two patients with OCD and their families, but not in additional patients or controls. They also found that a mutation called I425V, though rare, appeared in two unrelated study families, and suggest “it is likely to exist in other families with OCD and related disorders.”

In addition to the I425V mutation, the two original subjects and their two siblings had a “particular form” of yet another hSERT variant: two long alleles of the 5-HTTLPR polymorphism. This mutation, which is associated with increased expression and function of the serotonin transporter gene, “suggests a ‘double hit,’ or two changes, within the same gene,” the researchers report. “The combination of these changes, both of which increase serotonin transport by themselves, may explain the unusual severity and treatment resistance of the illnesses in the subjects and their siblings,” the team concluded.

Their research appears in the Oct. 23 issue of Molecular Psychiatry.

“This is a new model for neuropsychiatric genetics, the concept of two or maybe more within-gene modifications being important in each affected individual,” NIMH Director Thomas Insel said in a statement. “This is also probably the first report of a modification in a transporter gene resulting in a gain rather than a decrease in function.”

The serotonin transporter, or SERT, enables neurons, platelets, and other cells to accumulate serotonin, which plays a role in emotion. Transporters are “important sites for agents that treat psychiatric disorders,” the researcher said. Drugs like serotonin reuptake inhibitors that reduce the binding of serotonin to transporters “treat mental disorders effectively,” they said. In fact, SSRIs are used to treat around half of patients with OCD, “but those with the hSERT gene defect do not seem to respond to them,” according to the researchers.

— KL


Indiana Team Said Bacteria Mutate When ‘Starving,’ causing Antimicrobial Resistance

A report in the current issue of Molecular Biology has shown that genes in certain bacteria mutate when the bugs run out of food — significant because until now scientists had believed that gene mutations in bacteria occur when the organisms find themselves in “strange or stressful” circumstances.

Patricia Foster and Jill Layton, biologists at Indiana University in Bloomington found that as Escherichia coli cells begin to starve, the bacteria quadruple their expression of DNA Polymerase IV, a mutation-causing enzyme that is “notoriously bad” at copying DNA accurately. “The culprit,” the scientists discovered, is sigma-38, a stress protein that “appears to activate” the expression of the Pol IV gene.

These findings may also lead to a better understanding — and thus better diagnostic and therapeutic options — for dealing with bacteria that can mutate rapidly, especially those implicated in nosocomial, or hospital-acquired, infections.

“We’ve known that bacteria respond to different kinds of stress by activating 30 genes or so,” said Foster, who led the study. “We now know Pol IV is part of the response to starvation, which E. coli experience regularly during their life cycles.” She said this polymerase “may provide the bacterium with new properties that help them get out of difficulty by, for example, giving them the ability to use other food sources for growth.”

Before this research, scientists had believed that increased expression of Pol IV was limited to “weird, drastic circumstances, the kind which might force a bacterium to mutate or die,” the Indiana team said. But Foster and Layton “have shown that a very common situation in nature — one in which bacteria use up available food — is enough to cause bacteria to activate Pol IV’s gene, which in turn leads to more mutations.”

To be sure, genetic mutations are considered bad for bacteria; altered genes rarely work properly, and the bugs become susceptible to environmental factors such as existing antibiotics. However, mutations may also enable offspring bacteria to become resistant to these antibiotics — an important distinction because, as the US Food and Drug Administration has put it, “disease-causing microbes that have become resistant to drug therapy are an increasing public health problem” in the US.

To arrive at their results, the Indiana team studied Pol IV expression patterns in 24 experimental strains of E. coli. Some strains had a functional Pol IV, and some did not, they found. Also, some strains had a functional form of the stress protein sigma-38 — the amount of which increases during stationary phase, a slow-growth behavior caused by starvation — and some didn’t.

The researchers found that when the bacteria were under starving conditions, their Pol IV expression levels increased from basal levels of about 250 copies of Pol IV in a single cell — to as many as 1,000 copies. They also found that levels of Pol IV were equally low in E. coli strains that were missing a functional sigma-38 as they were in normal strains growing in non-starving conditions. This led Foster and Layton to conclude that sigma-38 helps control to what extent Pol IV is expressed.

— KL

Filed under

The Scan

Push Toward Approval

The Wall Street Journal reports the US Food and Drug Administration is under pressure to grant full approval to SARS-CoV-2 vaccines.

Deer Exposure

About 40 percent of deer in a handful of US states carry antibodies to SARS-CoV-2, according to Nature News.

Millions But Not Enough

NPR reports the US is set to send 110 million SARS-CoV-2 vaccine doses abroad, but that billions are needed.

PNAS Papers on CRISPR-Edited Cancer Models, Multiple Sclerosis Neuroinflammation, Parasitic Wasps

In PNAS this week: gene-editing approach for developing cancer models, role of extracellular proteins in multiple sclerosis, and more.