PSTPIP1 Gene

The PSTPIP1 gene (PSTPIP1 stands for Proline-Serine-Threonine Phosphatase Interacting Protein 1) is a protein-coding gene located on chromosome 15q24.3.The PSTPIP1 gene encodes a cytoskeletal protein that is highly expressed in hematopoietic tissues.

"Proline-serine-threonine phosphatase interaction protein 1" (PSTPIP1; also known as CD2BP1) is a cytoskeleton-associated adaptor protein that modulates T cell activation,16 cytoskeletal organization, and IL-1β release. Heterozygous mutations in the PSTPIP1 gene cause the dominantly inherited syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) (OMIM #604410). PAPA syndrome is a rare autosomal dominant autoinflammatory disorder typically caused by the missense mutations p.A230T (c.688G>A) and p.E250Q (c.748 G>C) in PSTPIP1. The mutations causing PAPA syndrome are thought to disrupt the interaction of PSTPIP1 with a protein tyrosine phophatase (PTP-PEST), a regulatory phosphatase, resulting in uncontrolled secretion of IL-1β , probably by binding to pyrin, which is mutated in patients with FMF.

Furthermore, the PSTPIP1 protein is involved in the regulation of the actin cytoskeleton. It functions by interacting with several different proteins involved in cytoskeletal organization and inflammatory processes. Thus, it binds to the cytoplasmic tail of CD2, an effector of T cell activation and adhesion, thereby downregulating adhesion triggered by CD2. Furthermore, the protein interacts with pyrin, which is found in association with the cytoskeleton in myeloid/monocytic cells and modulates immunoregulatory functions.

Thus, the PSTPIP1 gene and its gene product play an essential role in innate immunity and the inflammatory response.

Pathogenic mutations in the PSTPIP1 gene are associated with PSTPIP1-associated autoinflammatory diseases (PAIDs), particularly PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) and the closely related PAMI syndrome (PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome); furthermore, with pyoderma gangraenosum.

In pyoderma gangraenosum, a chronic inflammatory disease, aberrant splice variants of the PSTPIP1 transcript occur together with deletions of exons 9, 11 and 12 and exons 9-12. The combinations of aberrant splice variants result in frame shifts and premature stop codons associated with truncated proteins and loss of function of PSTPIP1 (Nesterovitch AB et al. 2011). The disease-causing mutations are thought to impair physiological signaling required to maintain an adequate inflammatory response.

1. Boursier G et al (2021) Phenotypic associations of PSTPIP1 sequence variances in PSTPIP1-Associated Autoinflammatory Diseases. J Invest Dermatol 141:1141-1147.
2. Li YR et al (2015) Genetic sharing and heritability of paediatric age of onset autoimmune diseases. Nat Commun 6:8442.
3. Nesterovitch AB et al (2011) Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with pyoderma gangrenosum. Clin Exp Dermatol 36:889-895.
4. Saito N et al (2018) Novel PSTPIP1 gene mutation in pyoderma gangrenosum, acne and suppurative hidradenitis syndrome. J Dermatol 45:e213-e214.