Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa
Open accessAbstract
Background: The autoinflammation 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 first 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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Mutations in PLCG2 that constitutively activate the enzyme contribute to autoinflammatory disorders and resistance mechanisms in cancer treatment.
“mutations in PLCG2 that constitutively activate the enzyme contribute to autoinflammatory disorders and resistance mechanisms in cancer treatment. 21 , 22 , 23”
From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [22]
The Introduction (page not available) reports constitutive PLCγ2 activation in PLAID and links an activating PLCG2 mutation to the autoinflammatory disorder APLAID, but explicitly says the APLAID mutation is not constitutively active. The Case Report (page not available) describes an activating PLCG2 mutation associated with resistance to the cancer drug ibrutinib, without saying that mutation constitutively activates the enzyme. Thus the disease and treatment-resistance links are supported, but the constitutive-activation qualifier is not supported for both. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAberrant functions of different PLCs and PI3Ks in disease development are well established.
“Although not covered in this review, the importance of aberrant functions of different PLCs and PI3Ks in disease development is well established and continues to expand [11,62,67,72,134–138].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [138]
The Case Report links a gain-of-function PLCγ2 mutation to disease in one patient, supporting the claim for that PLC. The Introduction distinguishes PLC isoforms, but the paper does not establish disease roles for different PLCs or for PI3Ks; the broader claim is not supported by this source alone. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA significant gain of function of PLCγ2 can lead to deleterious impacts on the immune system.
“These clearly indicate that a significant gain of function of PLCγ2 can lead to deleterious impacts on the immune system.”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [33]
Whole-blood assays revealed reduced production of IL-10 and IL-1β after LPS stimulation in APLAID.
“In contrast, whole-blood assays revealed a reduced production of IL-10 and IL-1β after LPS stimulation (110).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [110]
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- Authors
- Neves, J. F., Doffinger, R., Barcena-Morales, G., Martins, C., Papapietro, O., Plagnol, V., Curtis, J., Martins, M., Kumararatne, D., Cordeiro, A. I., Neves, C., Borrego, L. M., Katan, M., & Nejentsev, S.
- Affiliations
- Unidade Local de Saúde de São José (PT)
- Universidade Nova de Lisboa (PT)
- University of Cambridge (GB)
- University College London (GB)
- University of Lisbon (PT)
- Addenbrooke's Hospital (GB)
- Corresponding author
- Neves, João Farela
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2018-12-14
- Volume
- 9
- Pages
- 2863-2863
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC6302768
- OpenAlex
- W2905167632
- Cited by
- 79
- References
- 22
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 13 · 2021: 15 · 2020: 14 · 2019: 9
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Medical Research Council
- National Institute for Health Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- PLCγ2, gain-of-function mutations, cutis laxa, autoinflammation, primary immunodeficiency, inflammatory bowel disease, posterior uveitis, sensorineural hearing loss, ruxolitinib, NLRP3 inflammasome, IL-1β, IL-17, interferon-gamma, IL-10, interstitial pneumonitis
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cutis Laxa, DNA Mutational Analysis, Female, Humans, Immunologic Deficiency Syndromes, Infant, Newborn, Male, Pedigree, Inflammatory Bowel Diseases, Sequence Homology, Amino Acid, Mutation, Missense, Phospholipase C gamma, Hereditary Autoinflammatory Diseases
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