The genetic cause of a syndrome characterized by multiple frustrating and difficult-to-treat symptoms, including dizziness and lightheadedness, skin flushing and itching, gastrointestinal complaints, chronic pain, bone and joint problems, is now better understood.
Jonathan J. Lyons et al identified a genetic explanation for a syndrome characterized by multiple frustrating and difficult-to-treat symptoms. Image credit: Pheee.
Some people who experience these multiple symptoms have elevated levels of tryptase — a protein in the blood often associated with allergic reactions.
Multiple copies of the alpha tryptase (TPSAB1) gene drive these tryptase elevations and may contribute to the symptoms. That’s according to research by a team of researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), who published their findings in the journal Nature Genetics this week.
Previous studies have indicated that 4-6% of the general public has high tryptase levels. While not all of these people experience symptoms, many do, raising the possibility that this mildly prevalent trait in some cases drives the symptoms, although how it does so remains unclear.
“This work suggests that multiple TPSAB1 copies might underlie health issues that affect a substantial number of people. Identifying one genetic cause for high tryptase opens the door for us to develop strategies for diagnosing and treating people carrying this genetic change,” said NIAID Director Dr. Anthony Fauci, who was not involved in the study.
Previously, the team had observed that a combination of chronic and sometimes debilitating symptoms, such as hives, irritable bowel syndrome and overly flexible joints, runs in some families and is associated with high tryptase levels.
Many affected family members with high tryptase also reported symptoms consistent with disorders of autonomic nervous system function, including postural orthostatic tachycardia syndrome.
In their new study, the NIAID scientists describe how they identified a genetic cause of high tryptase by studying these families.
Initial analyses pointed the researchers to the TPSAB1 gene, and they designed a new lab test to detect the number of TPSAB1 copies.
Analysis of 96 affected and 41 unaffected members from 35 families confirmed that all affected family members had inherited multiple copies of TPSAB1.
The experiments suggested that the additional copies were leading to increased production and release of alpha tryptase protein from immune cells.
Moreover, the team found that additional gene copies were associated with more severe effects. Family members with three copies of the TPSAB1 gene had higher tryptase levels and reported experiencing more symptoms than those who had two copies.
The researchers next investigated this genetic change in a general population.
They assessed a group of patients who had their DNA sequenced for reasons unrelated to tryptase, as well as a group of healthy unrelated volunteers from the ClinSeq study — 172 people in total.
To the team’s surprise, all those with high blood levels of tryptase also had duplications of the TPSAB1 gene. Many people with the duplicate gene reported experiencing symptoms similar to those seen in the original group of severely affected families, including irritable bowel syndrome, skin flushing and itching.
“These families had gone for years without a medical diagnosis, and many had been told that some of their symptoms were ‘all in your head.’ These results not only provide a genetic explanation for the combination of symptoms that these patients experience, but also point the way to a potential solution,” said study senior author Dr. Joshua Milner, from NIAID’s Laboratory of Allergic Diseases.
“If we can devise a way to block alpha tryptase, we might be able to alleviate some or all of the symptoms related to elevated tryptase levels.”
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Jonathan J. Lyons et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nature Genetics, published online October 17, 2016; doi: 10.1038/ng.3696
This article is based on a press-release from NIH’s National Institute of Allergy and Infectious Diseases.
