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Browsing by Author "Nejentsev, S"

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  • Novel IL2RG Mutation Causes Leaky TLOWB+NK+ SCID With Nodular Regenerative Hyperplasia and Normal IL-15 STAT5 Phosphorylation
    Publication . Neves, JF; Martins, C; Cordeiro, AI; Neves, C; Plagnol, V; Curtis, J; Fabre, M; Bibi, S; Borrego, LM; Moshous, D; Nejentsev, S; Gilmour, K
    X-linked severe combined immunodeficiency disease (SCID) is caused by mutations in the interleukin (IL)-2 receptor γ (IL2RG) gene and patients usually present with a TBNK SCID phenotype. Nevertheless, a minority of these patients present with a TBNK phenotype, similar to the IL-7R-deficient patients. We report a patient with a novel missense p.Glu297Gly mutation in the IL2RG gene presenting with a leaky TBNK SCID with delayed onset, moderate susceptibility to infections, and nodular regenerative hyperplasia. He presents with preserved STAT5 tyrosine phosphorylation in response to IL-15 stimulation but not in response to IL-2 and IL-7, resulting in the NK phenotype.
    2019Journal article Open access Show more
  • Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa
    Publication . Neves, JF; Doffinger, R; Barcena-Morales, G; Martins, C; Papapietro, O; Plagnol, V; Curtis, J; Martins, M; Kumararatne, D; Cordeiro, AI; Neves, C; Borrego, LM; Katan, M; Nejentsev, S
    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.
    2018Journal article Open access Show more
  • Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation
    Publication . Ouahed, J; Kelsen, JR; Spessott, WA; Kooshesh, K; Sanmillan, ML; Dawany, N; Sullivan, KE; Hamilton, KE; Slowik, V; Nejentsev, S; Farela Neves, J; Flores, H; Chung, WK; Wilson, A; Anyane-Yeboa, K; Wou, K; Jain, P; Field, M; Tollefson, S; Dent, MH; Li, D; Naito, T; McGovern, DPH; Kwong, AC; Taliaferro, F; Ordovas-Montanes, J; Horwitz, BH; Kotlarz, D; Klein, C; Evans, J; Dorsey, J; Warner, N; Elkadri, A; Muise, AM; Goldsmith, J; Thompson, B; Engelhardt, KR; Cant, AJ; Hambleton, S; Barclay, A; Toth-Petroczy, A; Vuzman, D; Carmichael, N; Bodea, C; Cassa, CA; Devoto, M; Maas, RL; Behrens, EM; Giraudo, CG; Snapper, SB
    Background and aims: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. Methods: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. Results: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Conclusion: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.
    2021Journal article Open access Show more