title: Spontaneous insertion of a b2 element in the ptpn6 gene drives a systemic autoinflammatory disease in mice resembling neutrophilic dermatosis in humans.
abstract: We found a spontaneous autosomal mutation in a mouse leading to neutrophil infiltration with ulceration in the upper dermis of homozygous offspring. These animals had increased neutrophil numbers, associated with normal lymphocyte count, in peripheral blood and bone marrow, suggesting a myeloproliferative disorder; however, granulocyte precursor proliferation in bone marrow was actually reduced (because circulating neutrophils were less susceptible to apoptosis). Neutrophil infiltration of the skin and other organs and high serum levels of immunoglobulins and autoantibodies, cytokines, and acute-phase proteins were additional abnormalities, all of which could be reduced by high-dose corticosteroid treatment or neutrophil depletion by antibodies. Use of genome-wide screening localized the mutation within an 0.4-Mbp region on mouse chromosome 6. We identified insertion of a B2 element in exon 6 of the Ptpn6 gene (protein tyrosine phosphatase, non-receptor type 6; also known as Shp-1). This insertion involves amino acid substitutions that significantly reduced the enzyme activity in mice homozygous for the mutation. Disease onset was delayed, and the clinical phenotype was milder than the phenotypes of other Ptpn6-mutants described in motheaten (me, mev) mice; we designated this new genotype as Ptpn6(meB2/meB2) and the phenotype as meB2. This new phenotype encompasses an autoinflammatory disease showing similarities to many aspects of the so-called neutrophilic dermatoses, a heterogeneous group of skin diseases with unknown etiology in humans.
authors: Department of Dermatology, Rush University Medical Center, Chicago, Illinois, USA.
authors: Andrew B
authors: AB
authors: Nesterovitch
authors: Sandor
authors: S
authors: Szanto
authors: Andrea
authors: A
authors: Gonda
authors: Tamas
authors: T
authors: Bardos
authors: Katalin
authors: K
authors: Kis-Toth
authors: Vyacheslav A
authors: VA
authors: Adarichev
authors: Katalin
authors: K
authors: Olasz
authors: Sheida
authors: S
authors: Ghassemi-Najad
authors: Mark D
authors: MD
authors: Hoffman
authors: Michael D
authors: MD
authors: Tharp
authors: Katalin
authors: K
authors: Mikecz
authors: Tibor T
authors: TT
authors: Glant
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000737:chemistry; D002874:Chromosome Mapping; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D009504:Neutrophils / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000502:physiology*; D012871:Skin Diseases / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D001323:Autoantibodies; D007136:Immunoglobulins; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse