Table I.

JAK STAT pathway genetics and in vivo functions in mice and humans

	Knockout phenotype	Mendelian Disorders	Somatic GOF mutations	GWAS links
JAK1	Perinatal lethality Impaired responses to multiple cytokines including type I and II IFNs, IL-2, IL-4, IL-10, IL-27	LOF: Mycobacterial disease, warts parasitic and fungal infection Progressive T lymphopenia, increased IgG and IgA levels, GOF: atopy, autoimmunity	Acute lymphoblastic leukemia Acute myeloid leukemia	JIA, MS, autoimmune thyroid disease, CRP levels, acute myeloid leukemia, lymphocyte and eosinophil counts, body mass and height
JAK2	Embryonic lethal, absence of definitive hematopoiesis		Myeloproliferative neoplasms: Polycythemia vera, Essential thrombocythaemia Acute lymphoblastic leukemia Acute myeloid leukemia Chronic myelogenous leukemia	SLE, allergy, eczema, AS, RA, T1DM, Psoriasis, IBD, cholesterol level, eosinophil basophil platelet erythrocyte count, body height
JAK3	Defective T and B cell development, Impaired responses to IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 immunodeficiency	LOF: T-B+NK- SCID	Myeloproliferative neoplasms Acute lymphoblastic leukemia Myelomonocytic leukaemia NK Lymphoma/Leukemia T cell Lymphoma/Leukemia
TYK2	Bacterial and viral infection Impaired responses to type I interferon, IL-12, IL-23 and IL-10	LOF: Mycobacterial disease and infections with other bacteria and viruses		SLE, RA, JIA, psoriasis, AS, IBD, MS, T1DM, T2DM, COVID-19, mycobacterial susceptibility, platelet and lymphocyte count,
STAT1	Bacterial and viral infection	LOF: Mycobacterial disease, viral infections GOF: Autoimmunity Mucocutaneous candidiasis, Invasive fungal infections, viral susceptibility	T cell Lymphoma-Leukemia Other hematopoietic and solid organ cancers	SLE, JIA, reticulocyte count, eosinophil and neutrophil count, brain measurement, body height
STAT2	Impaired type I IFN responses Viral susceptibility	LOF: Severe viral infections mitochondrial abnormalities,	Hematopoietic and solid organ cancers	Psoriasis, psoriatic arthritis, diabetic retinopathy, lymphocyte count, height
STAT3	Impaired placental development, defective signaling by multiple cytokines	LOF: Hyperimmunoglobulin E recurrent infection syndrome GOF: Multisystem autoimmune disease	NK Cell Lymphoma-Leukemia T cell Lymphoma -Leukemia B cell lymphoma Myelodysplastic syndrome Solid organ tumors (Head and neck, breast, skin, gastrointestinal, neural cancers)	eczema, IBD, MS, SLE, T2DM, Mean corpuscular volume, CRP, blood pressure, mosquito bite reaction,
STAT4	Impaired IL-12 and IL-23 signaling, and type 1 immune responses	LOF: fungal disease	Hematopoietic and solid organ cancers	SLE, RA, Sjogren's syndrome
STAT5A	Defective mammary gland development and impaired GM-CSF signaling		Leukemia Lymphoma Solid organ tumors (Head and neck, breast, skin, gastrointestinal, neural, prostate cancers)	Asthma, cholesterol, bone density, obesity
STAT5B	Impaired growth, liver gene expression, innate lymphocyte homeostasis	Growth hormone insensitivity, immunodeficiency, autoimmunity atopy	Acute and chronic lymphocytic leukemia Lymphoma Large granular lymphocytic leukemia Solid organ tumors (Head and neck, breast, skin, gastrointestinal, neural, prostate cancers) Atopy, autoimmunity, eosinophilia	Asthma, allergy, cholesterol level, neutrophil, eosinophil, and lymphocyte count, bone density, blood pressure, obesity
STAT6	Impaired IL-4 and IL-13 signaling, and type 2 immune response	GOF: treatment resistant allergic disease	B Cell Lymphoma Follicular lymphoma Other hematopoietic and solid organ cancers	Asthma, allergy, eczema,eosinophil count, IgE levels, mosquito bite size,

AS- ankylosing spondyloarthritis; CRP-C-reactive protein, GOF – gain of function; IBD – inflammatory bowel disease, JIA – juvenile idiopathic arthritis; LOF – loss of function; MS – multiple sclerosis; RA- rheumatoid arthritis; SCID – severe combined immunodeficiency; SLE-systemic lupus erythematosus, T1DM – type 1 diabetes mellitus; T2DM-type 2 diabetes mellitus; (https://www.ebi.ac.uk/gwas)