Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa

Frontiers in Immunology

Sergey Nejentsev¹  João Farela Neves²  Catarina Martins²  Rainer Doffinger³  Dinakantha Kumararatne³  Olivier Papapietro⁴  James Curtis⁴  Marta Martins⁵  Luis Miguel Borrego⁶  Gabriela Barcena-Morales⁷  Ana Isabel Cordeiro⁸  Conceição Neves⁸  Matilda Katan⁹  Vincent Plagnol^1,10 

[1] 0Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, Netherlands;CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, Portugal;Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom;Department of Medicine, University of Cambridge, Cambridge, United Kingdom;Faculty of Medicine, University of Lisbon, Lisbon, Portugal;Immunoallergy Department, Hospital CUF Descobertas, Lisbon, Portugal;Laboratorio de Inmunologia, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Mexico City, Mexico;Primary Immunodeficiencies Unit, Hospital Dona Estefânia—CHLC, EPE, Lisbon, Portugal;Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom;University College London Genetics Institute, University College London, London, United Kingdom;

关键词: APLAID;    PLCγ2;    cutis laxa;    sensorineural deafness;    IL-10;    IL-1b;   

DOI  :  10.3389/fimmu.2018.02863

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown