Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma
Authors: Minskaia Ekaterina , Maimaris Jesmeen , Jenkins Persephone , Albuquerque Adriana S. , Hong Ying , Eleftheriou Despina , Gilmour Kimberly C. , Grace Richard , Moreira Fernando , Grimbacher Bodo ,   NIHR Bioresource-Rare Diseases Consortium, Adhya Zoe , Alachkar Hana , Anantharachagan Ariharan , Antrobus Richard , Arumugakani Gururaj , Bacchelli Chiara , Baxendale Helen , Bethune Claire , Bibi Shahnaz , Boardman Barbara , Booth Claire , Browning Michael , Brownlie Mary , Burns Siobhan , Chandra Anita , Clifford Hayley , Cooper Nichola , Davies Sophie , Dempster John , Devlin Lisa , Doffinger Rainer , Drewe Elizabeth , Edgar David , Egner William , El-Shanawany Tariq , Gaspar Bobby , Ghurye Rohit , Gilmour Kimberley , Goddard Sarah , Gordins Pavel , Grigoriadou Sofia , Hackett Scott , Hague Rosie , Harper Lorraine , Hayman Grant , Herwadkar Archana , Hughes Stephen , Huissoon Aarnoud , Jolles Stephen , Jones Julie , Kelleher Peter , Klein Nigel , Kuijpers Taco , Kumararatne Dinakantha , Laffan James , Allen Hana Lango , Lear Sara , Longhurst Hilary , Lorenzo Lorena , Maimaris Jesmeen , Manson Ania , McDermott Elizabeth , Millar Hazel , Mistry Anoop , Morrisson Valerie , Murng Sai , Nasir Iman , Nejentsev Sergey , Noorani Sadia , Oksenhendler Eric , Ponsford Mark , Qasim Waseem , Quinn Ellen , Quinti Isabella , Richter Alex , Samarghitean Crina , Sargur Ravishankar , Savic Sinisa , Seneviratne Suranjith , Sewall Carrock , Shackley Fiona , Simeoni Ilenia , Smith Kenneth G. C. , Staples Emily , Stauss Hans , Steele Cathal , Thaventhiran James , Thomas Moira , Thrasher Adrian , Welch Steve , Willcocks Lisa , Workman Sarita , Worth Austen , Yeatman Nigel , Yong Patrick , Ashford Sofie , Bradley John , Fletcher Debra , Hammerton Tracey , James Roger , Kingston Nathalie , Ouwehand Willem , Penkett Christopher , Raymond F. Lucy , Stirrups Kathleen , Veltman Marijke , Young Tim , Brown Matthew , Clements-Brod Naomi , Davis John , Dewhurst Eleanor , Erwood Marie , Frary Amy , Linger Rachel , Martin Jennifer , Papadia Sofia , Rehnstrom Karola , Astle William , Attwood Antony , Bleda Marta , Carss Keren , Daugherty Louise , Deevi Sri , Graf Stefan , Greene Daniel , Halmagyi Csaba , Haimel Matthias , Hu Fengyuan , Matser Vera , Meacham Stuart , Megy Karyn , Shamardina Olga , Titterton Catherine , Tuna Salih , Turro Ernest , Yu Ping , von Ziegenweldt Julie , Furnell Abigail , Mapeta Rutendo , Staines Simon , Stephens Jonathan , Whitehorn Deborah , Rayner-Matthews Paula , Watt Christopher , Morris Emma C. , Burns Siobhan O. 
Published: June 2023

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.

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