What Is CRIA Syndrome?

After 20 years of unsuccessful diagnosis, new research from the National Human Genome Research Institute (NHGRI) has revealed the mechanics behind a mysterious auto-inflammatory disease. Known as CRIA syndrome, the disease is caused by mutations in the RIPK1 gene and triggers debilitating symptoms such as severe abdominal pain, fever, swollen lymph nodes, headaches, gastrointestinal problems and enlarged liver and spleen. The findings were published in the journal Nature, with NHGRI scientific director Daniel Kastner, M.D., Ph.D. saying that while CRIA syndrome isn't fatal it can have a tremendously negative impact on quality of life.

Exploring cause and effect

To investigate the causes of the condition, Kastner and his team analysed the genomes of each patient. After sequencing specific gene regions, they found that one gene in particular - RIPK1 - was mutated in all patients. Known as "missense" mutations, the variation changed a single DNA letter which subsequently altered the amino acid levels distributed to the encoded protein.

"It was as if lightning had struck three times in the same place," says Kastner. "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."

Inflammation and cell death programming in overdrive

The RIPK1 gene creates codes for the RIPK1 protein, which plays an important role in managing inflammation and programming cell death. To regulate this function, a different protein "cuts" RIPK1 at a certain point in the sequence. For all patients suffering from the mysterious symptoms, the team observed DNA mutations in the location where RIPK1 is usually cut off. This allowed the RIPK1 protein to operate in overdrive and accelerate inflammation and cell death.

After identifying the cause-effect relationship between RIPK1 mutations and the associated symptoms, Kastner and his team named the disease cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome. Working with researchers from the Walter and Eliza Hall Institute in Australia, the team create specialised mouse models to investigate the molecular mechanisms of CRIA syndrome and potentially develop a treatment strategy or cure. When trialled on patients, an immune system suppressing drug called tocilizumab significantly reduced the severity of CRIA syndrome symptoms. Moving forward, the researchers hope to explore how tocilizumab targets CRIA syndrome and whether the drug could be used to treat other auto-inflammatory conditions.

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