Genetic mutation linked to rare inflammatory bowel disease

© iStock/Feodora Chiosea

A genetic mutation that weakens virus-fighting activity in the immune system may explain the cause of common bowel diseases, researchers say.

Scientists from Johns Hopkins Medicine, in collaboration with national and international researchers, have identified a genetic mutation in a small number of children with a rare type of inflammatory bowel disease. They say that this discovery could help to define the cause of more common bowel diseases and lead to more targeted treatments for gut conditions.

The study has been published in Human Genetics.

Anthony Guerreiro Jr., M.D, Ph.D., M.S., Director of the Very Early Onset Inflammatory Bowel Disease Clinic and Assistant Professor of Pediatrics at the Johns Hopkins University School of Medicine, said: “We aimed to see if children have a greater genetic susceptibility for this type of inflammatory bowel disease because they develop it so young,”

Very early onset inflammatory bowel disease

Unlike other inflammatory bowel diseases, very early onset inflammatory bowel disease is diagnosed in patients before the age of six, occurring in four out of every 100,000 births worldwide. In such young patients, the disease does not typically respond to anti-inflammatory medications, and surgery is sometimes required to remove all or parts of the colon.

Inflammatory bowel diseases are chronic, inflammatory conditions — including Crohn’s disease and ulcerative colitis — that occur when immune cells in the intestines are overactivated, causing sustained inflammation in the gut. These diseases are thought to be caused by multiple genetic mutations and environmental factors, such as diet and pollution, as well as disruptions to the makeup of gut bacteria. Common treatments include prescription drugs that curb inflammation.

Since the most common characteristic of bowel diseases is inflammation, scientists have long suspected genetic links between the immune system and bowel conditions.

Mutations in the IFIH1 gene

In the study, scientists collected tissue samples from 24 patients with very early onset inflammatory bowel disease seen at The Johns Hopkins Hospital and Johns Hopkins Children’s Center and performed whole exome sequencing – a method that looks at the protein-producing areas of a gene to identify mutations.

Of the 24 patients, mutations were found in four patients in parts of a gene called IFIH1, which produces a protein involved in the virus-fighting branch of the immune system. Other genetic sequencing studies have also linked the IFIH1 gene to inflammatory bowel diseases, and the current research backs up the gene’s involvement in very early onset inflammatory bowel disease.

As the number of patients in the first round of sequencing was small, the researchers turned to a Johns Hopkins-developed online database called GeneMatcher, which contains genetic variations from people worldwide. Guerrerio and GeneMatcher co-founder Nara Sobreira, M.D, Ph.D, Assistant Professor of Genetics and Pediatrics at the Johns Hopkins University of Medicine, found an additional 18 patients with very early onset inflammatory bowel disease being studied at both the NIH and in Padova, Italy.

The combined research teams found IFIH1 mutations in four of the 18 new patients, bringing the total of IFIH1 mutations found to eight out of the 42 patients. Among the IFIH1 mutations, the researchers discovered nine mutations which resulted in abnormal production of a protein called MDA5. In the eight patients with the mutations, MDA5 function was much lower than normal.

When functioning properly, MDA5 is a part of the inborn immune system that helps fight off viruses in the gut. Using protein assays that mimicked the activity of normal and abnormal MDA5, the researchers found that, in each patient with the IFIH1 mutation, the MDA5 proteins only partially worked, but not enough to do their job of battling viruses. The researchers suspect this loss of function in the protein causes the improper activation of the immune system, triggering the inflammation that leads to very early onset inflammatory bowel disease.

The researchers also believe that the partially functioning MDA5 proteins protect patients from more severe and rare immune diseases, such as Singleton-Merton syndrome and Aicardi-Goutières syndrome, that are associated with no MDA5 production.

Sobreira said: “When you look at the physical changes associated with IFIH1 mutations, there are a wide range and they are really very different.

“It’s crucial to know that these different variations in the same gene can cause these different characteristics.”

Implications for treatment

The researchers hope that their findings will help to improve understanding of the genetic cause of diseases and inform treatment options. They also believe the research provides additional evidence of the link between inflammatory bowel diseases and the virus-fighting part of the body’s immune response.



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