TY - JOUR
T1 - Spontaneous insertion of a B2 element in the Ptpn6 gene drives a systemic autoinflammatory disease in mice resembling neutrophilic dermatosis in humans
AU - Nesterovitch, Andrew B.
AU - Szanto, Sandor
AU - Gonda, Andrea
AU - Bardos, Tamas
AU - Kis-Toth, Katalin
AU - Adarichev, Vyacheslav A.
AU - Olasz, Katalin
AU - Ghassemi-Najad, Sheida
AU - Hoffman, Mark D.
AU - Tharp, Michael D.
AU - Mikecz, Katalin
AU - Glant, Tibor T.
N1 - Funding Information:
Supported in part by philanthropic support from the J.O. Galante Endowment Chair at Rush University Medical Center , Chicago (T.T.G.), the Grainger Foundation , Forest Park, IL (T.T.G., K.M.), and the Clark W. Finnerud MD Endowment Chair (M.D.T.).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2011/4
Y1 - 2011/4
N2 - 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 Ptpn6meB2/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.
AB - 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 Ptpn6meB2/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.
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U2 - 10.1016/j.ajpath.2010.12.053
DO - 10.1016/j.ajpath.2010.12.053
M3 - Article
C2 - 21435452
AN - SCOPUS:79953667487
VL - 178
SP - 1701
EP - 1714
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -