Over the last 20 years, three families have been unsuspectingly linked by an unknown illness. Researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, and other organizations have now identified the cause of the illness, a new disease called CRIA syndrome. The results were published in the journal Nature.

Investigator’s Monumental Discovery

NHGRI scientific director Daniel Kastner, M.D., Ph.D., a pioneer in the field of autoinflammatory diseases, and his team discovered CRIA, which has symptoms including fevers, swollen lymph nodes, severe abdominal pain, gastrointestinal problems, headaches and, in some cases, abnormally enlarged spleen and liver.

The disorder has characteristics typical of an autoinflammatory disease, where the immune system appears to be activated without any apparent trigger. Although the condition is not life-threatening, patients have persistent fever and swollen lymph nodes from childhood to old age, as well as other symptoms that can lead to lifelong pain and disability.

When confronted by patients’ symptoms, who were first seen at the NIH Clinical Center, researchers looked for infections and cancer as the cause. After those were ruled out, they sought answers in the genome, a person’s complete set of DNA. Kastner and his team sequenced gene regions across the genome and discovered only one gene—RIPK1—to be consistently different in all patients.

Key Findings

Researchers identified a specific type of variation in the patients: a single DNA letter at a specific location incorrectly changed. This change can alter the amino acid added to the encoded protein. These are called “missense” mutations. Remarkably, each of the three families had its own unique missense mutation affecting the very same DNA letter in the RIPK1 gene. Each affected person had one mutant and one normal copy of the gene, while the unaffected family members had two normal copies of the gene.

The researchers also looked at 554 people with sporadic unexplained fever, swollen glands and other symptoms or diseases, and then at over a quarter million people from public sequence databases to see if they encountered the same RIPK1 mutations. When they did not find such mutations elsewhere, it was clear that they were onto something new.

“It was as if lightning had struck three times in the same place,” said Kastner, who led the NHGRI team. “This discovery underscores the tremendous power of combining astute clinical observation, state-of-the-art DNA sequencing, and the sharing of sequence data in large publicly-accessible databases. We live in a very special time.”

Further Understanding Needed

Although the researchers made the connection between CRIA syndrome and RIPK1 mutations, they still needed to understand the molecular mechanisms involved in the disease. To do this, Kastner and his team collaborated with Najoua Laloui, Ph.D., and John Silke, Ph.D., at the Walter and Eliza Hall Institute in Australia, who made specialized mouse models with similar RIPK1 mutations as seen in CRIA patients.

Potential Treatment

Kastner and his team also worked to find a treatment for CRIA syndrome. Seven patients with the condition were given therapies that are known to reduce inflammation. While drugs such as etanercept and anakinra, which are routinely used to treat autoinflammatory and chronic diseases such as rheumatoid arthritis, had little effect on the patients, one biological drug called tocilizumab did. Tocilizumab, a drug that suppresses the immune system, reduced the severity and frequency of CRIA syndrome symptoms in five out of seven patients in some cases with life-changing effects.

Hirotsugu Oda, M.D., Ph.D., a post-doctoral researcher in Kastner’s laboratory and co-first author of the paper, said: “As a physician-scientist, the most thrilling experience to me was to hear the mother of a CRIA patient say that her son was a completely different, healthy child after the tocilizumab treatment. Through the genetic diagnosis, we were able to contribute to the treatment of a few patients. This is, after all, the ultimate goal.”

Lead Investigators

Daniel Kastner, M.D., Ph.D., NHGRI scientific director and a pioneer in the field of autoinflammatory diseases

Hirotsugu Oda, M.D., Ph.D., a post-doctoral researcher in Kastner’s laboratory and co-first author of the paper

About the National Human Genome Research Institute (NHGRI) 

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found here.

About the National Institutes of Health (NIH)

NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit their website.

Call to Action: Learn more about the intricacies of this new disease and subsequent research by following the source link below or reaching out to Prabarna Ganguly, Ph.D. of the National Human Genome Research Institute (NHGRI) via email or at 301-480-5289.

Source: National Institutes of Health

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