Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://doi.org/10.3389/fimmu.2018.02863 |
Resumo: | Background: The auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the PLCG2 gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome. Case: We describe a new APLAID patient who presented with vesiculopustular rash in the 1st weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa. Her disease has been refractory to most treatments, including IL1 blockers and a trial with ruxolitinib has been attempted. Results: In this patient, we found a unique de novo heterozygous missense L848P mutation in the PLCG2 gene, predicted to affect the PLCγ2 structure. Similarly to S707Y, the L848P mutation led to the increased basal and EGF-stimulated PLCγ2 activity in vitro. Whole blood assays showed reduced production of IFN-γ and IL-17 in response to polyclonal T-cell stimulation and reduced production of IL-10 and IL-1β after LPS stimulation. Reduced IL-1β levels and the lack of clinical response to treatment with IL-1 blockers argue against NLRP3 inflammasome hyperactivation being the main mechanism mediating the APLAID pathogenesis. Conclusion: Our findings indicate that L848P is novel a gain-of-function mutation that leads to PLCγ2 activation and suggest cutis laxa as a possible clinical manifestations of the APLAID syndrome. |
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Novel PLCG2 Mutation in a Patient With APLAID and Cutis LaxaAPLAIDauto-inflammatory syndromescutis laxaIL-10IL-1bPLCγ2sensorineural deafnessImmunology and AllergyImmunologyBackground: The auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the PLCG2 gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome. Case: We describe a new APLAID patient who presented with vesiculopustular rash in the 1st weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa. Her disease has been refractory to most treatments, including IL1 blockers and a trial with ruxolitinib has been attempted. Results: In this patient, we found a unique de novo heterozygous missense L848P mutation in the PLCG2 gene, predicted to affect the PLCγ2 structure. Similarly to S707Y, the L848P mutation led to the increased basal and EGF-stimulated PLCγ2 activity in vitro. Whole blood assays showed reduced production of IFN-γ and IL-17 in response to polyclonal T-cell stimulation and reduced production of IL-10 and IL-1β after LPS stimulation. Reduced IL-1β levels and the lack of clinical response to treatment with IL-1 blockers argue against NLRP3 inflammasome hyperactivation being the main mechanism mediating the APLAID pathogenesis. Conclusion: Our findings indicate that L848P is novel a gain-of-function mutation that leads to PLCγ2 activation and suggest cutis laxa as a possible clinical manifestations of the APLAID syndrome.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)RUNNeves, João FarelaDoffinger, RainerBarcena-Morales, GabrielaMartins, CatarinaPapapietro, OlivierPlagnol, VincentCurtis, JamesMartins, MartaKumararatne, DinakanthaCordeiro, Ana IsabelNeves, ConceiçãoBorrego, Luis MiguelKatan, MatildaNejentsev, Sergey2019-01-24T23:38:20Z20182018-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1application/pdfhttps://doi.org/10.3389/fimmu.2018.02863eng1664-3224PURE: 11348498http://www.scopus.com/inward/record.url?scp=85059928837&partnerID=8YFLogxKhttps://doi.org/10.3389/fimmu.2018.02863info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:28:15Zoai:run.unl.pt:10362/58538Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:33:16.881863Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
title |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
spellingShingle |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa Neves, João Farela APLAID auto-inflammatory syndromes cutis laxa IL-10 IL-1b PLCγ2 sensorineural deafness Immunology and Allergy Immunology |
title_short |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
title_full |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
title_fullStr |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
title_full_unstemmed |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
title_sort |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
author |
Neves, João Farela |
author_facet |
Neves, João Farela Doffinger, Rainer Barcena-Morales, Gabriela Martins, Catarina Papapietro, Olivier Plagnol, Vincent Curtis, James Martins, Marta Kumararatne, Dinakantha Cordeiro, Ana Isabel Neves, Conceição Borrego, Luis Miguel Katan, Matilda Nejentsev, Sergey |
author_role |
author |
author2 |
Doffinger, Rainer Barcena-Morales, Gabriela Martins, Catarina Papapietro, Olivier Plagnol, Vincent Curtis, James Martins, Marta Kumararatne, Dinakantha Cordeiro, Ana Isabel Neves, Conceição Borrego, Luis Miguel Katan, Matilda Nejentsev, Sergey |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) Centro de Estudos de Doenças Crónicas (CEDOC) RUN |
dc.contributor.author.fl_str_mv |
Neves, João Farela Doffinger, Rainer Barcena-Morales, Gabriela Martins, Catarina Papapietro, Olivier Plagnol, Vincent Curtis, James Martins, Marta Kumararatne, Dinakantha Cordeiro, Ana Isabel Neves, Conceição Borrego, Luis Miguel Katan, Matilda Nejentsev, Sergey |
dc.subject.por.fl_str_mv |
APLAID auto-inflammatory syndromes cutis laxa IL-10 IL-1b PLCγ2 sensorineural deafness Immunology and Allergy Immunology |
topic |
APLAID auto-inflammatory syndromes cutis laxa IL-10 IL-1b PLCγ2 sensorineural deafness Immunology and Allergy Immunology |
description |
Background: The auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the PLCG2 gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome. Case: We describe a new APLAID patient who presented with vesiculopustular rash in the 1st weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa. Her disease has been refractory to most treatments, including IL1 blockers and a trial with ruxolitinib has been attempted. Results: In this patient, we found a unique de novo heterozygous missense L848P mutation in the PLCG2 gene, predicted to affect the PLCγ2 structure. Similarly to S707Y, the L848P mutation led to the increased basal and EGF-stimulated PLCγ2 activity in vitro. Whole blood assays showed reduced production of IFN-γ and IL-17 in response to polyclonal T-cell stimulation and reduced production of IL-10 and IL-1β after LPS stimulation. Reduced IL-1β levels and the lack of clinical response to treatment with IL-1 blockers argue against NLRP3 inflammasome hyperactivation being the main mechanism mediating the APLAID pathogenesis. Conclusion: Our findings indicate that L848P is novel a gain-of-function mutation that leads to PLCγ2 activation and suggest cutis laxa as a possible clinical manifestations of the APLAID syndrome. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018 2018-01-01T00:00:00Z 2019-01-24T23:38:20Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://doi.org/10.3389/fimmu.2018.02863 |
url |
https://doi.org/10.3389/fimmu.2018.02863 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1664-3224 PURE: 11348498 http://www.scopus.com/inward/record.url?scp=85059928837&partnerID=8YFLogxK https://doi.org/10.3389/fimmu.2018.02863 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
1 application/pdf |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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