Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with pyoderma gangrenosum

Summary Background. Pyoderma gangrenosum (PG) is a rare, noninfectious form of skin ulceration, typically accompanied by neutrophilic infiltration. Several familial cases have been reported, suggesting the involvement of genetic factors in the aetiology of PG. Two mutations (A230T and E250Q) in the PSTPIP1 gene, encoding proline–serine–threonine phosphatase‐interacting protein (PSTPIP)1 have been identified in patients with PAPA (pyogenic sterile arthritis with PG and acne) syndrome, a rare autoinflammatory disorder with autosomal dominant inheritance. Aim. The aim of this study was to sequence PSTPIP1 complementary cDNA and genomic DNA for mutations, and to identify genetic polymorphisms in the promoter region of PSTPIP1 in patients with PG. Methods. The genomic region and cDNA of the PSTPIP1 gene were sequenced from peripheral blood leucocytes of 14 patients with PG and 20 healthy controls. Results. One patient (PG1) had aberrant splicing variants of the PSTPIP1 transcript with deletions of exons 9, 11 and 12 and of exons 9–12 together, and all other patients with PG carried deletions of exon 11 and of 11–12. We also identified a novel mutation (G258A) in patient PG3, and novel polymorphisms [(CCTG)6 and (CCTG)8 tandem repeats] in the promoter region of the PSTPIP1 gene. Conclusion. All combinations of aberrant splicing variants had frame shifts and premature stop codons leading to truncated proteins and loss of function of PSTPIP1. The (CCTG)n tandem repeats in the promoter region of PSTPIP1 had no association with PG. The mutations G258A and R52Q are predicted by the improved prediction algorithm to have a possibly damaging effect on PSTPIP1 function.