Neves, JF;
Doffinger, R;
Barcena-Morales, G;
Martins, C;
Papapietro, O;
Plagnol, V;
Curtis, J;
... Nejentsev, S; + view all
(2018)
Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa.
Frontiers in Immunology
, 9
, Article 2863. 10.3389/fimmu.2018.02863.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fimmu.2018.02863 |
| Publisher version: | https://doi.org/10.3389/fimmu.2018.02863 |
| Language: | English |
| Additional information: | © 2018 Farela Neves, Doffinger, Barcena-Morales, Martins, Papapietro, Plagnol, Curtis, Martins, Kumararatne, Isabel Cordeiro, Neves, Miguel Borrego, Katan and Nejentsev. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | APLAID, PLCγ2, cutis laxa, sensorineural deafness, IL-10, IL-1b, auto-inflammatory syndromes |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10071092 |
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