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Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma

2023; Springer Science+Business Media; Volume: 43; Issue: 7 Linguagem: Inglês

10.1007/s10875-023-01530-7

1573-2592

Ekaterina Minskaia, Jesmeen Maimaris, Persephone Jenkins, Adriana S. Albuquerque, Ying Hong, Despina Eleftheriou, Kimberly Gilmour, Richard Grace, Fernando Moreira, Bodo Grimbacher, Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Barbara Boardman, Claire Booth, Michael Browning, Mary Brownlie, Siobhan O. Burns, Anita Chandra, Hayley Clifford, Nichola Cooper, Sophie Davies, John Dempster, Lisa Devlin, Rainer Döffinger, Elizabeth Drewe, David Edgar, William Egner, Tariq El‐Shanawany, Bobby Gaspar, Rohit Ghurye, Kimberly Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Stephen Hughes, Aarnoud Huissoon, Stephen Jolles, Julie R. Jones, Peter Kelleher, Nigel Klein, Taco W. Kuijpers, Dinakantha Kumararatne, James Laffan, Hana Lango Allen, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Ellie Quinn, Isabella Quinti, Alexander Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith L. Seneviratne, Carrock Sewall, Fiona Shackley, Ilenia Simeoni, Kenneth G. C. Smith, Emily Staples, Hans J. Stauss, Cathal Steele, James Thaventhiran, Moira Thomas, Adrian J. Thrasher, Steve Welch, Lisa Willcocks, Sarita Workman, Austen Worth, Nigel Yeatman, Patrick Yong, Sofie Ashford, John S. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Willem H. Ouwehand, Christopher Penkett, F. Lucy Raymond, Kathleen Stirrups, Marijke Veltman, Timothy M. Young, Matthew A. Brown, Emma Clement, John M. Davis, Eleanor Dewhurst, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnström, William J. Astle, Antony Attwood, Marta Bleda, Keren Carss, Louise C. Daugherty, Sri V. V. Deevi, Stefan Gräf, Daniel Greene, Csaba Halmagyi, Matthias Haimel, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Mégy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ernest Turro, Ping Yu, Julie von Ziegenweldt, Abigail Furnell, Rutendo Mapeta, Simon Staines, Jonathan Stephens, Deborah Whitehorn, Paula Rayner-Matthews, C. Ian F. Watt, Emma Morris, Siobhan O. Burns,

Immunodeficiency and Autoimmune Disorders

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.245 words.