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Conference Paper: Autosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection

TitleAutosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection
Authors
Issue Date2013
PublisherAsian Society for Pediatric Research (ASPR) and the Perinatal Society of Malaysia (PSM).
Citation
The 2013 Joint Scientific Meeting of the 9th Asian Society for Pediatric Research Congress and the 20th Perinatal Society of Malaysia Annual Congress (ASPR / PSM 2013), Sarawak, Malaysia, 9-12 May 2013. In Programme & Abstract Book, 2013, p. 41, abstract no. FP 151 How to Cite?
AbstractBackground: Penicillium marneffei infection is indigenous to Southeast Asia. Majority of cases occur in patients with AIDS and secondary immunodeficiencies. We previously reported 4 HIV-negative children with chronic mucocutaneous candidiasis (CMC) and severe penicilliosis. Hyper-IgE syndrome was diagnosed in one of them, but extensive genetic studies on IL12-IFNγ axis, CARD9 and AIRE were unrevealing for the rest. Recently, STAT1 hyperphosphorylation causing defective Th1 and Th17 immunity is recognized as a cause of CMC. Objective: To investigate the genetic and functional defects of STAT1 signaling in children affected by penicilliosis. Methods: Targeted sequencing of STAT1 gene or total exome sequencing was performed in 3 patients with CMC and penicilliosis. PBMCs were isolated from patients and normal controls. Intracellular STAT1 phosphorylation (pSTAT1) towards interferon-α and interferon-γ stimulation was evaluated by flow cytometry. Cytokine production in PBMCs towards PMA and ionomycin stimulation was assessed. PBMCs were co-cultured with live Candida albicans and P. marneffei to evaluate interferon-γ response. Results: Heterozygous STAT1 missense mutations were identified in all 3 patients. Two mutations were located in the coiled-coil domain (P1 and P2) and one in the DNA-binding domain (P3). All 3 patients recovered from penicilliosis, but P1 eventually died of fulminant aspergillosis. The percentage of pSTAT1-positive PBMCs induced by interferon-α and interferon-γ was significantly higher in all 3 patients than normal controls, indicating that they had gain-of-function mutations. PBMCs from all patients displayed defective interferon-γ and interleukin-17 production towards PMA and PMA plus ionomycin, respectively. Interferon-γ production induced by C. albicans and P. marneffei in P2 was significantly lower than normal controls. Conclusions: For the first time, we demonstrated STAT1 gain-of-function mutation as an important and novel genetic etiology of invasive mycosis including penicilliosis and aspergillosis. Penicilliosis should be regarded as an indicator disease for primary immunodeficiencies in children without HIV infection unless proven otherwise.
DescriptionConference Theme: Inflammatory Basis of Perinatal and Childhood Diseases
Symposium / Free Paper 4: Immunology
Persistent Identifierhttp://hdl.handle.net/10722/185076

 

DC FieldValueLanguage
dc.contributor.authorLee, PPWen_US
dc.contributor.authorMao, Hen_US
dc.contributor.authorYang, Wen_US
dc.contributor.authorChan, KWen_US
dc.contributor.authorHo, MHKen_US
dc.contributor.authorLee, TLen_US
dc.contributor.authorTu, WWen_US
dc.contributor.authorLau, YL-
dc.date.accessioned2013-07-15T10:28:42Z-
dc.date.available2013-07-15T10:28:42Z-
dc.date.issued2013en_US
dc.identifier.citationThe 2013 Joint Scientific Meeting of the 9th Asian Society for Pediatric Research Congress and the 20th Perinatal Society of Malaysia Annual Congress (ASPR / PSM 2013), Sarawak, Malaysia, 9-12 May 2013. In Programme & Abstract Book, 2013, p. 41, abstract no. FP 151en_US
dc.identifier.urihttp://hdl.handle.net/10722/185076-
dc.descriptionConference Theme: Inflammatory Basis of Perinatal and Childhood Diseases-
dc.descriptionSymposium / Free Paper 4: Immunology-
dc.description.abstractBackground: Penicillium marneffei infection is indigenous to Southeast Asia. Majority of cases occur in patients with AIDS and secondary immunodeficiencies. We previously reported 4 HIV-negative children with chronic mucocutaneous candidiasis (CMC) and severe penicilliosis. Hyper-IgE syndrome was diagnosed in one of them, but extensive genetic studies on IL12-IFNγ axis, CARD9 and AIRE were unrevealing for the rest. Recently, STAT1 hyperphosphorylation causing defective Th1 and Th17 immunity is recognized as a cause of CMC. Objective: To investigate the genetic and functional defects of STAT1 signaling in children affected by penicilliosis. Methods: Targeted sequencing of STAT1 gene or total exome sequencing was performed in 3 patients with CMC and penicilliosis. PBMCs were isolated from patients and normal controls. Intracellular STAT1 phosphorylation (pSTAT1) towards interferon-α and interferon-γ stimulation was evaluated by flow cytometry. Cytokine production in PBMCs towards PMA and ionomycin stimulation was assessed. PBMCs were co-cultured with live Candida albicans and P. marneffei to evaluate interferon-γ response. Results: Heterozygous STAT1 missense mutations were identified in all 3 patients. Two mutations were located in the coiled-coil domain (P1 and P2) and one in the DNA-binding domain (P3). All 3 patients recovered from penicilliosis, but P1 eventually died of fulminant aspergillosis. The percentage of pSTAT1-positive PBMCs induced by interferon-α and interferon-γ was significantly higher in all 3 patients than normal controls, indicating that they had gain-of-function mutations. PBMCs from all patients displayed defective interferon-γ and interleukin-17 production towards PMA and PMA plus ionomycin, respectively. Interferon-γ production induced by C. albicans and P. marneffei in P2 was significantly lower than normal controls. Conclusions: For the first time, we demonstrated STAT1 gain-of-function mutation as an important and novel genetic etiology of invasive mycosis including penicilliosis and aspergillosis. Penicilliosis should be regarded as an indicator disease for primary immunodeficiencies in children without HIV infection unless proven otherwise.-
dc.languageengen_US
dc.publisherAsian Society for Pediatric Research (ASPR) and the Perinatal Society of Malaysia (PSM).-
dc.relation.ispartofASPR / PSM 2013en_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleAutosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infectionen_US
dc.typeConference_Paperen_US
dc.identifier.emailLee, PPW: ppwlee@hku.hken_US
dc.identifier.emailMao, H: hwmau@hku.hken_US
dc.identifier.emailYang, W: yangwl@hkucc.hku.hken_US
dc.identifier.emailChan, KW: kwchan@hku.hken_US
dc.identifier.emailHo, MHK: marcoho@hku.hken_US
dc.identifier.emailLee, TL: leetsz@hkucc.hku.hken_US
dc.identifier.emailTu, WW: wwtu@hku.hken_US
dc.identifier.emailLau, YL: lauylung@hku.hk-
dc.identifier.authorityLee, PPW=rp00462en_US
dc.identifier.authorityMao, H=rp01595en_US
dc.identifier.authorityYang, W=rp00524en_US
dc.identifier.authorityTu, WW=rp00416en_US
dc.description.naturepublished_or_final_version-
dc.identifier.hkuros216052en_US
dc.identifier.spage41, abstract no. FP 151-
dc.identifier.epage41, abstract no. FP 151-

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