Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder

Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
Human Molecular Genetics (Impact Factor: 6.68). 05/2002; 11(8):961-9.
Source: PubMed

ABSTRACT PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne, OMIM #604416) and familial recurrent arthritis (FRA) are rare inherited disorders of early onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction. We recently localized the genes for PAPA syndrome and FRA to chromosome 15q and suggested that they are the same disorder. We have now established this by the identification of co-segregating disease-causing mutations in the CD2-binding protein 1 (CD2BP1; GenBank accession no XM 044569) gene in the two reported families with this disorder. E250Q or A230T amino acid substitutions occur within a domain highly homologous to yeast cleavage furrow-associated protein CDC15. CD2BP1 and its murine ortholog, proline-serine-threonine phosphatase interacting protein (PSTPIP1), are adaptor proteins known to interact with PEST-type protein tyrosine phosphatases (PTP). Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins. Previous evidence supports the integral role of CD2BP1 and its interacting proteins in actin reorganization during cytoskeletal-mediated events. We hypothesize that the disease-causing mutations that we have identified compromise physiologic signaling necessary for the maintenance of proper inflammatory response. Accordingly we suggest classification of PAPA syndrome as an autoinflammatory disease. This CD2BP1-mediated biochemical pathway(s) may function in common inflammatory disorders with apparent etiological overlap, such as rheumatoid arthritis and inflammatory bowel disease.

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    • "Autoinflammatory diseases were considered monogenic, such as PAPA (pyogenic sterile arthritis, PG, and acne) syndrome in which a mutation in the PSTPIP1 gene causes overproduction of IL1 and resultant neutrophil-mediated reactions in skin and organs [16]. Neutrophilic diseases share some clinical features with monogenic autoinflammatory disorders such as periodic fever and neutrophil infiltration in the skin and other organs. "
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    • "Point mutations involved in PSTPIP1 and its family member, PSTPIP2, are known to be involved in autoinflammatory diseases. Point mutations of PSTPIP1 in humans are found in PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum and acne), where there is severely reduced binding between the mutant protein and PTP-PEST [75]. Another example of inflammatory disease can be found in mice possessing a point mutation in the MAYP/PSTPIP2 protein [76] [77] [78]. "
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