Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review

Abstract

PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an autosomal dominant, hereditary auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. These mutations produce a hyper-phosphorylated PSTPIP1 protein and alter its participation in activation of the "inflammasome" involved in interleukin-1 (IL-1β) production. Overproduction of IL-1β is a clear molecular feature of PAPA syndrome. Ongoing research is implicating other biochemical pathways that may be relevant to the distinct pyogenic inflammation of the skin and joints characteristic of this disease. This review summarizes the recent and rapidly accumulating knowledge on these molecular aspects of PAPA syndrome and related disorders.

Keywords: Auto-inflammatory disease; CD2BP1; IL-1β.; PAPA syndrome; PSTPIP1; PTP-PEST; anakinra; microarray transcript profiling; neutrophils; pyrin.

Fig. (1)

Pyoderma gangrenosum in a child with PAPA syndrome.

Fig. (2)

PSTPIP1 protein schematic. FCH, coiled-coil, and SH3 domains are shown. Asterisks denote the relative positions of the A230T and E250Q mutations. Interacting proteins are shown below single domains for simplicity. It should be noted that some in vitro studies indicate more complex binding patterns than depicted here.

Fig. (3)

Schematic depiction of the “inflammasome.” IL-1β and IL-18 are substrates for caspase.

Fig. (4)

Modular analyses of PAPA blood gene expression reveals over-expression of neutrophil and platelet-related genes. mRNA expression level differences in PBMCs between PAPA patients and age- and sex-matched healthy controls were obtained by statistical group comparison. We further performed modular analyses as described in [67, 68]. Briefly, genes are assigned a priori to particular functional units (i. e. modules) as derived from extensive analyses of expression in PBMCs. Statistical comparisons are then made between disease groups and healthy groups on a module-by-module basis, where the proportion of under- or over-expressed genes in the module is depicted in the cartoon by differences in color and intensity. This approach simplifies analysis and produces a distinct “fingerprint” of disease. A complete list of differentially expressed gene transcripts in PAPA syndrome individuals versus controls is available upon request.