Seven people who suffer from a previously unknown disorder that causes fever every two to four weeks have now been diagnosed by researchers who finally identified the genetic cause of their disease.
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Scientists from Australia and the US conducted a genetic analysis that identified the mutation causing their disease, which has now been called CRIA syndrome.
The team found that the autoinflammatory disease CRIA (cleavage-resistant RIPK1-induced autoinflammatory) syndrome is caused by a mutation in a cell death component called RIPK1.
The finding could pave the way for the development of cell death inhibitors for the treatment of autoinflammatory disorders.
The research was led by Najoua Lalaoui and John Silke from the Walter and Eliza Hall Institute of Medical Research in Australia and Steven Boyden, Hirotsugu Oda, and Dan Kastner from the National Human Genome Research Institute at the National Institutes of Health (NIH), US.
Fever every two-to-four weeks for their entire lives
The seven individuals, who are from three families in the US and were aged between 10 and 82 when they were first evaluated, had all experienced fever every two to four weeks for their entire lives.
During episodes of fever, their lymph nodes would become painful and swollen, and their body temperature could reach as high as 41°C.
"You can imagine that having a fever and swollen lymph nodes every two weeks is not a good life," says Lalaoui. Some also suffered from other symptoms, including nausea, diarrhea, and mouth ulcers.
To investigate what might be causing the symptoms, the team analyzed the patients' exomes – the regions of DNA that code for all proteins in the body.
Discovering the mutation
As recently reported in the journal Nature, the analysis revealed that all seven individuals have a mutation in the RIPK1 gene. The disease caused by this mutation has never been described before, says Lalaoui.
"We sequenced the entire exome of each patient and discovered unique mutations in the exact same amino acid of RIPK1 in each of the three families," says Boyden. "It is remarkable, like lightning striking three times in the same place. Each of the three mutations has the same result -- it blocks cleavage of RIPK1 -- which shows how important RIPK1 cleavage is in maintaining the normal function of the cell."
Next, the researchers genetically engineered mice to have the mutation and gave them fragments of bacteria. The bacteria triggered an exaggerated immune response in the animals that caused cell death.
"We showed that mice with mutations in the same location in RIPK1 as in the CRIA syndrome patients had a similar exacerbation of inflammation,"
Najoua Lalaoui, Walter and Eliza Hall Institute of Medical Research, Australia
Cell death pathways have developed a series of inbuilt mechanisms that regulate inflammatory signals and cell death because the alternative is so potentially hazardous, Lalaoui explains: "However, in this disease, the mutation in RIPK1 is overcoming all the normal checks and balances that exist, resulting in uncontrolled cell death and inflammation."
The discovery could lead to better treatments
The discovery may lead to more effective treatments for the seven individuals, as well as others who are diagnosed with the same disease. In China, another team of researchers has identified two more families with the same mutation and similar symptoms.
Currently, some of the patients in the US are being treated with expensive anti-inflammatory drugs such as interleukin-6 inhibitor, but the drugs are not always effective, and they can cost more than $30,000 a year.
Understanding the molecular mechanism by which CRIA syndrome causes inflammation affords an opportunity to get right to the root of the problem."
Dan Kastner, National Institutes of Health (NIH) investigator
Lalaoui agrees that drugs specifically targeting RIPK1 may be a better option. She says such drugs are currently being developed, although none have been approved yet.
"RIPK1 inhibitors may be just what the doctor ordered for these patients. The discovery of CRIA syndrome also suggests a possible role for RIPK1 in a broad spectrum of human illnesses, such as colitis, arthritis and psoriasis," says Kastner.
Tao, P. et al. (2019). A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature. DOI: https://doi.org/10.1038/s41586-019-1830-y
Lalaloui, N. et al. (2019). Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature. DOI: https://doi.org/10.1038/s41586-019-1828-5