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Conference Paper: Autosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection
Title | Autosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection |
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Authors | |
Issue Date | 2013 |
Publisher | Asian 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? |
Abstract | Background: 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. |
Description | Conference Theme: Inflammatory Basis of Perinatal and Childhood Diseases Symposium / Free Paper 4: Immunology |
Persistent Identifier | http://hdl.handle.net/10722/185076 |
DC Field | Value | Language |
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dc.contributor.author | Lee, PPW | en_US |
dc.contributor.author | Mao, H | en_US |
dc.contributor.author | Yang, W | en_US |
dc.contributor.author | Chan, KW | en_US |
dc.contributor.author | Ho, MHK | en_US |
dc.contributor.author | Lee, TL | en_US |
dc.contributor.author | Tu, WW | en_US |
dc.contributor.author | Lau, YL | - |
dc.date.accessioned | 2013-07-15T10:28:42Z | - |
dc.date.available | 2013-07-15T10:28:42Z | - |
dc.date.issued | 2013 | en_US |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/185076 | - |
dc.description | Conference Theme: Inflammatory Basis of Perinatal and Childhood Diseases | - |
dc.description | Symposium / Free Paper 4: Immunology | - |
dc.description.abstract | Background: 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.language | eng | en_US |
dc.publisher | Asian Society for Pediatric Research (ASPR) and the Perinatal Society of Malaysia (PSM). | - |
dc.relation.ispartof | ASPR / PSM 2013 | en_US |
dc.title | Autosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection | en_US |
dc.type | Conference_Paper | en_US |
dc.identifier.email | Lee, PPW: ppwlee@hku.hk | en_US |
dc.identifier.email | Mao, H: hwmau@hku.hk | en_US |
dc.identifier.email | Yang, W: yangwl@hkucc.hku.hk | en_US |
dc.identifier.email | Chan, KW: kwchan@hku.hk | en_US |
dc.identifier.email | Ho, MHK: marcoho@hku.hk | en_US |
dc.identifier.email | Lee, TL: leetsz@hkucc.hku.hk | en_US |
dc.identifier.email | Tu, WW: wwtu@hku.hk | en_US |
dc.identifier.email | Lau, YL: lauylung@hku.hk | - |
dc.identifier.authority | Lee, PPW=rp00462 | en_US |
dc.identifier.authority | Mao, H=rp01595 | en_US |
dc.identifier.authority | Yang, W=rp00524 | en_US |
dc.identifier.authority | Tu, WW=rp00416 | en_US |
dc.description.nature | published_or_final_version | - |
dc.identifier.hkuros | 216052 | en_US |
dc.identifier.spage | 41, abstract no. FP 151 | - |
dc.identifier.epage | 41, abstract no. FP 151 | - |