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Familial Autoinflammatory Disease Traced to Missense Mutation in MEFV

NEW YORK (GenomeWeb) – An international team of researchers has tracked down the genetic source of an autoinflammatory disease afflicting a Belgian family.

A dozen members of the family, spanning three generations, have what the researchers have dubbed pyrin-associated autoinflammation with neutrophilic dermatosis, or PAAND, which is a dominantly inherited disease. They suffer from severe skin lesions, fever, pain, and fatigue, among other symptoms.

The research team led by KU Leuven's Adrian Liston and Carine Wouters carried out genome-wide linkage analysis on 20 family members and performed exome sequencing on two trios from pedigree, as they reported today in Science Translational Medicine. From this, they homed in on a substitution in the MEFV gene, which encodes the pyrin protein. Additional functional studies indicated that the mutation triggers inflammasome activation as well as the production of IL-1β.

"The PAAND mutation causes the body to respond as if there is a bacterial skin infection," first author Seth Masters, a professor at the Walter and Elisa Hall Institute of Medical Research in Australia, said in a statement. "This leads to the skin making the inflammatory protein interleukin‐1β, which causes skin lesions, fevers, and pain."

The researchers performed whole-genome genotyping on 20 members of the Flemish family, including 12 affected and eight healthy people, and identified a region of chromosome 16 with a genome-wide significant LOD score. After then sequencing the whole exomes of two trios from the lineage, the researchers sifted through the more than 8,700 variants within that linkage region to uncover a synonymous variant in RPL3L and a missense mutation in MEFV.

The missense mutation in MEFV, they noted, segregated with disease. The mutation, a C-to-G substitution in exon 2 of MEFV, leads to a serine-to- arginine substitution at position 242 in the pyrin protein.

Recessive mutations in MEFV cause familial Mediterranean fever (FMF), an autoinflammatory disease marked by fever and the inflammation of serous membranes, such as those of the heart, brain, or testicles, but the researchers argued that PAAND and FMF are distinct diseases. The PAAND mutation in MEFV falls outside the region typically associated with FMF, and the PAAND symptoms differ from those of FMF, they noted.

By searching through a number of genetic and hereditary autoinflammatory disease database, Masters and his colleagues uncovered a handful of other people with the pyrin S242R mutation, including a family in the UK, that had largely similar symptoms as the Belgian family.

Through functional studies, the researchers found that this mutation disrupts pyrin regulation to cause disease. In particular, they reported that the S242R mutation leads to increased ASC speck formation, which is a marker of inflammasome activation — something that nearby heterozygous variants linked to Sweet syndrome and variants linked to FMF don't cause. The variant further leads to caspase-1 activation and increased production of the p20 subunit that is then incorporated into the inflammasome speck.

At the same time, the mutation leads to the loss of the 14-3-3 binding motif and the loss of S242 phosphorylation, leading to increased IL-1β production.

This, the researchers noted, mimics the effects of pathogen sensing and tricks the body into thinking it is under attack.

It also suggests a possible treatment. One patient in the UK was treated with anakinra, a rheumatoid arthritis drug that targets IL-1, after failing corticosteroid and methotrexate treatment, and has since had her clinical symptoms resolve.

The researchers are now pursuing a large trial among the Flemish patients.

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