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: 6.39). 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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Available from: Rose Veile, Sep 26, 2015
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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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    ABSTRACT: A 7-year-old boy with high grade fever (39°C) and warm, erythematous, and indurated plaque above the left knee was referred. According to the previous records of this patient, these indurated plaques had been changed toward abscesses formation and then spontaneous drainage had occurred after about 6 to 7 days, and finally these lesions healed with scars. In multiple previous admissions, high grade fever, leukocytosis, and a noticeable increase in erythrocyte sedimentation rate and C-reactive protein were noted. After that, until 7th year of age, he had shoulder, gluteal, splenic, kidney, and left thigh lesions and pneumonia. The methylprednisolone pulse (30 mg/kg) was initiated with the diagnosis of Sweet’s syndrome. After about 10–14 days, almost all of the laboratory data regressed to nearly normal limits. After about 5 months, he was admitted again with tachypnea and high grade fever and leukocytosis. After infusion of one methylprednisolone pulse, the fever and tachypnea resolved rapidly in about 24 hours. In this admission, colchicine (1 mg/kg) was added to the oral prednisolone after discharge. In the periodic fever and neutrophilic dermatosis, the rheumatologist should search for sterile abscesses in other organs.
    Clinical Medicine: Case Reports 12/2014; 2014 (2014)(320920). DOI:10.1155/2014/320920
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    • "which codifies the CD2-binding protein 1 (CD2BP1), enclosed in the pyrin-mediated inflammatory pathway [113]. In the case of a PSTPIP1 mutation, the CD2BP1-pyrin link is facilitated; hence, the percentage of CD2BP1 binding to pyrin is higher, determining a proinflammatory state [114]. PAPAs starts in the first or second decade and is characterized by sterile pyogenic pauciarticular arthritis, cystic acne, ulcerative lesions occurring on the lower extremities, and pyogenic abscesses at the injection sites; cultures from the synovial liquid and skin lesions are characteristically negative [115]. "
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    ABSTRACT: The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.
    Mediators of Inflammation 07/2014; 2014:948154. DOI:10.1155/2014/948154 · 3.24 Impact Factor
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    • "More recently, new disease entities such as PASH syndrome (PG, acne, and suppurative hidradenitis) and PAPA syndrome (pyogenic arthritis, PG, and acne) are described in the literature as part of the spectrum of autoinflammatory disorders distinct from allergic, autoimmune, and infectious processes.5 PAPA syndrome is associated with genetic mutations involved in innate immune response regulation,6 while no genetic links have been detected in patients with PASH syndrome.5 "
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    ABSTRACT: Pyoderma gangrenosum (PG) is a rare dermatological condition characterized by the rapid progression of a painful, necrolytic ulcer with an irregular, undermined border and commonly affects the lower extremities, mainly in the pretibial area. The diagnosis of PG is not easy. Due to lack of diagnostic laboratory test and histopathological findings indicative of PG, it is often misdiagnosed as an infection. This results in delayed or inappropriate treatment of the condition, which leads to devastating consequences such as limb amputation and death. We report a rare case of a 51-year-old female who was initially diagnosed as having infected ulcers and underwent serial debridements, which resulted in extensive PG at three different sites (abdominal, left thigh, and sacral). This case highlights the challenges in diagnosing PG, emphasizes the key clinical features to aid diagnosis, and the clinical consequences of delayed or misdiagnosis of this condition.
    Clinical, Cosmetic and Investigational Dermatology 03/2014; 7:105-9. DOI:10.2147/CCID.S60229
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