title: Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses.
abstract: We have found a B2 repeat insertion in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6) in a mouse that developed a skin disorder with clinical and histopathological features resembling those seen in human neutrophilic dermatoses. Neutrophilic dermatoses are a group of complex heterogeneous autoinflammatory diseases that all demonstrate excessive neutrophil infiltration of the skin. Therefore, we tested the cDNA and genomic DNA sequences of PTPN6 from patients with Sweet's syndrome (SW) and pyoderma gangrenosum and found numerous novel splice variants in different combinations. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were the most common in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1.7-kbp deletion in the promoter region of the PTPN6 gene. Although full-length PTPN6 was detected in all other patients with either pyoderma gangrenosum or SW, it was always associated with splice variants: a partial deletion of exon 4 with the complete deletion of exon 5, alterations that were not detected in healthy controls. The defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses.
authors.affiliation: Department of Dermatology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nesterovitch
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Gyorfy
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hoffman
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Moore
authors.forename: Nada
authors.initials: N
authors.lastname: Elbuluk
authors.forename: Beata
authors.initials: B
authors.lastname: Tryniszewska
authors.forename: Tibor A
authors.initials: TA
authors.lastname: Rauch
authors.forename: Melinda
authors.initials: M
authors.lastname: Simon
authors.forename: Sewon
authors.initials: S
authors.lastname: Kang
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: Michael D
authors.initials: MD
authors.lastname: Tharp
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D001483:Base Sequence; D016207:Cytokines / Q000378:metabolism; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009504:Neutrophils / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012871:Skin Diseases / Q000235:genetics*
chemical_list: D016207:Cytokines; D010744:Phosphoric Monoester Hydrolases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6