Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency
Background: Generalized pustular psoriasis (GPP; MIM 614204) is a rare multisystemic autoinflammatory disease, characterized by episodes of acute generalized erythema and scaling developed with the spread of numerous sterile pustules. Adult-onset immunodeficiency syndrome (AOID) with anti-interferon...
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MDPI AG
2022-12-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/1/103 |
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| author | Piranit Kantaputra Teerada Daroontum Mati Chuamanochan Suteeraporn Chaowattanapanit Worrachet Intachai Bjorn Olsen Thanapat Sastraruji Sissades Tongsima Chumpol Ngamphiw Jatupol Kampuansai Timothy C. Cox Salin Kiratikanon |
| author_facet | Piranit Kantaputra Teerada Daroontum Mati Chuamanochan Suteeraporn Chaowattanapanit Worrachet Intachai Bjorn Olsen Thanapat Sastraruji Sissades Tongsima Chumpol Ngamphiw Jatupol Kampuansai Timothy C. Cox Salin Kiratikanon |
| author_sort | Piranit Kantaputra |
| collection | DOAJ |
| description | Background: Generalized pustular psoriasis (GPP; MIM 614204) is a rare multisystemic autoinflammatory disease, characterized by episodes of acute generalized erythema and scaling developed with the spread of numerous sterile pustules. Adult-onset immunodeficiency syndrome (AOID) with anti-interferon-γ autoantibodies is an immunodeficiency disorder associated with disruptive IFN-γ signaling. Methods: Clinical examination and whole exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Histopathological and immunohistochemical studies were performed. Results: WES identified four Thai patients presenting with similar pustular phenotypes—two with a diagnosis of GPP and the other two with AOID—who were found to carry the same rare TGFBR2 frameshift mutation c.458del; p.Lys153SerfsTer35, which is predicted to result in a marked loss of functional TGFBR2 protein. The immunohistochemical studied showed overexpression of IL1B, IL6, IL17, IL23, IFNG, and KRT17, a hallmark of psoriatic skin lesions. Abnormal TGFB1 expression was observed in the pustular skin lesion of an AOID patient, suggesting disruption to TGFβ signaling is associated with the hyperproliferation of the psoriatic epidermis. Conclusions: This study implicates disruptive TGFBR2-mediated signaling, via a shared truncating variant, c.458del; p.Lys153SerfsTer35, as a “predisposing risk factor” for GPP and AOID. |
| first_indexed | 2024-03-09T12:36:46Z |
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| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T12:36:46Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-43c04f74c0074700816823bc5211d7172023-11-30T22:23:34ZengMDPI AGGenes2073-44252022-12-0114110310.3390/genes14010103Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset ImmunodeficiencyPiranit Kantaputra0Teerada Daroontum1Mati Chuamanochan2Suteeraporn Chaowattanapanit3Worrachet Intachai4Bjorn Olsen5Thanapat Sastraruji6Sissades Tongsima7Chumpol Ngamphiw8Jatupol Kampuansai9Timothy C. Cox10Salin Kiratikanon11Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDivision of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandDivision of Dermatology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40000, ThailandCenter of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, ThailandDepartment of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USADental Research Center, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, ThailandNational Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani 12120, ThailandNational Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani 12120, ThailandDepartment of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, ThailandDepartments of Oral & Craniofacial Sciences and Pediatrics, School of Dentistry and School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USADivision of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandBackground: Generalized pustular psoriasis (GPP; MIM 614204) is a rare multisystemic autoinflammatory disease, characterized by episodes of acute generalized erythema and scaling developed with the spread of numerous sterile pustules. Adult-onset immunodeficiency syndrome (AOID) with anti-interferon-γ autoantibodies is an immunodeficiency disorder associated with disruptive IFN-γ signaling. Methods: Clinical examination and whole exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Histopathological and immunohistochemical studies were performed. Results: WES identified four Thai patients presenting with similar pustular phenotypes—two with a diagnosis of GPP and the other two with AOID—who were found to carry the same rare TGFBR2 frameshift mutation c.458del; p.Lys153SerfsTer35, which is predicted to result in a marked loss of functional TGFBR2 protein. The immunohistochemical studied showed overexpression of IL1B, IL6, IL17, IL23, IFNG, and KRT17, a hallmark of psoriatic skin lesions. Abnormal TGFB1 expression was observed in the pustular skin lesion of an AOID patient, suggesting disruption to TGFβ signaling is associated with the hyperproliferation of the psoriatic epidermis. Conclusions: This study implicates disruptive TGFBR2-mediated signaling, via a shared truncating variant, c.458del; p.Lys153SerfsTer35, as a “predisposing risk factor” for GPP and AOID.https://www.mdpi.com/2073-4425/14/1/103adult-onset immunodeficiency syndromeanti-interferon-γ autoantibodyTGFBR2 mutationgeneralized pustular psoriasispredisposing risk factorpustular skin reaction |
| spellingShingle | Piranit Kantaputra Teerada Daroontum Mati Chuamanochan Suteeraporn Chaowattanapanit Worrachet Intachai Bjorn Olsen Thanapat Sastraruji Sissades Tongsima Chumpol Ngamphiw Jatupol Kampuansai Timothy C. Cox Salin Kiratikanon Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency Genes adult-onset immunodeficiency syndrome anti-interferon-γ autoantibody TGFBR2 mutation generalized pustular psoriasis predisposing risk factor pustular skin reaction |
| title | Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency |
| title_full | Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency |
| title_fullStr | Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency |
| title_full_unstemmed | Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency |
| title_short | Loss of Function <i>TGFBR2</i> Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency |
| title_sort | loss of function i tgfbr2 i variant as a contributing factor in generalized pustular psoriasis and adult onset immunodeficiency |
| topic | adult-onset immunodeficiency syndrome anti-interferon-γ autoantibody TGFBR2 mutation generalized pustular psoriasis predisposing risk factor pustular skin reaction |
| url | https://www.mdpi.com/2073-4425/14/1/103 |
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