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

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.

Immunomodulator agent-related lymphoproliferative disorders

“…One patient had pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), an inherited autosomal dominant disorder associated with mutation in the CD2 binding protein 1 gene (CD2BP1) on chromosome 15. 13 The IAR-LPD were diagnosed a median of 2 years following institution of the immunomodulator agent therapy (range 6 weeks to 7 years among the nine patients with available data). All seven patients with atypical lymphoid proliferations were male, whereas most of the lymphomas (8/11, 72%) occurred in female patients (P ¼ 0.004).…”

Critical role for inflammasome-independent IL-1β production in osteomyelitis

“…Mutation in the highly homologous Pombe Cdc15 homology (PCH) family member, PSTPIP1, causes a rare genetic disorder known as pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome in humans (22). It was discovered that the PAPA-inducing mutation in PSTPIP1 results in aberrant inflammasome activation and IL-1β-driven pathology in patients, suggesting that PSTPIP1 is a novel negative regulator of inflammasomes (23)(24)(25)(26).…”

“…PSTPIP1, which shares marked sequence and structural homology with PSTPIP2 (19)(20)(21), has recently been identified as a negative regulator of inflammasome activation (22)(23)(24). Furthermore, inflammasome-mediated production of IL-1β by macrophages has been found to play instrumental roles in the pathogenesis of numerous autoinflammatory diseases.…”

A Case of Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne(PAPA) Syndrome Accompanied by Nephrosclerosis, Splenomegaly and Intestinal Lesions

“…Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominantly inherited autoinflammatory disorder (OMIM ID #604410) caused by a missense mutation in PSTPIP1, the gene for proline/serine/threonine phosphatase-interacting protein 1 (PSTPIP-1) [1,2]. Typically, pyogenic sterile arthritis recurs in childhood and is often triggered by minor trauma.…”