Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa
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...
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2018-12-01
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doaj-b006da5dea034c7dba115a83f60110232020-11-24T22:02:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-12-01910.3389/fimmu.2018.02863427716Novel PLCG2 Mutation in a Patient With APLAID and Cutis LaxaJoão Farela Neves0João Farela Neves1Rainer Doffinger2Gabriela Barcena-Morales3Catarina Martins4Olivier Papapietro5Vincent Plagnol6James Curtis7Marta Martins8Dinakantha Kumararatne9Ana Isabel Cordeiro10Conceição Neves11Luis Miguel Borrego12Luis Miguel Borrego13Matilda Katan14Sergey Nejentsev15Sergey Nejentsev16Primary Immunodeficiencies Unit, Hospital Dona Estefânia—CHLC, EPE, Lisbon, PortugalCEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, PortugalDepartment of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United KingdomLaboratorio de Inmunologia, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Mexico City, MexicoCEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, PortugalDepartment of Medicine, University of Cambridge, Cambridge, United KingdomUniversity College London Genetics Institute, University College London, London, United KingdomDepartment of Medicine, University of Cambridge, Cambridge, United KingdomFaculty of Medicine, University of Lisbon, Lisbon, PortugalDepartment of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United KingdomPrimary Immunodeficiencies Unit, Hospital Dona Estefânia—CHLC, EPE, Lisbon, PortugalPrimary Immunodeficiencies Unit, Hospital Dona Estefânia—CHLC, EPE, Lisbon, PortugalCEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, PortugalImmunoallergy Department, Hospital CUF Descobertas, Lisbon, PortugalStructural and Molecular Biology, Division of Biosciences, University College London, London, United KingdomDepartment of Medicine, University of Cambridge, Cambridge, United Kingdom0Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, NetherlandsBackground: 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.https://www.frontiersin.org/article/10.3389/fimmu.2018.02863/fullAPLAIDPLCγ2cutis laxasensorineural deafnessIL-10IL-1b |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
João Farela Neves João Farela Neves Rainer Doffinger Gabriela Barcena-Morales Catarina Martins Olivier Papapietro Vincent Plagnol James Curtis Marta Martins Dinakantha Kumararatne Ana Isabel Cordeiro Conceição Neves Luis Miguel Borrego Luis Miguel Borrego Matilda Katan Sergey Nejentsev Sergey Nejentsev |
spellingShingle |
João Farela Neves João Farela Neves Rainer Doffinger Gabriela Barcena-Morales Catarina Martins Olivier Papapietro Vincent Plagnol James Curtis Marta Martins Dinakantha Kumararatne Ana Isabel Cordeiro Conceição Neves Luis Miguel Borrego Luis Miguel Borrego Matilda Katan Sergey Nejentsev Sergey Nejentsev Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa Frontiers in Immunology APLAID PLCγ2 cutis laxa sensorineural deafness IL-10 IL-1b |
author_facet |
João Farela Neves João Farela Neves Rainer Doffinger Gabriela Barcena-Morales Catarina Martins Olivier Papapietro Vincent Plagnol James Curtis Marta Martins Dinakantha Kumararatne Ana Isabel Cordeiro Conceição Neves Luis Miguel Borrego Luis Miguel Borrego Matilda Katan Sergey Nejentsev Sergey Nejentsev |
author_sort |
João Farela Neves |
title |
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
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 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-12-01 |
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. |
topic |
APLAID PLCγ2 cutis laxa sensorineural deafness IL-10 IL-1b |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.02863/full |
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