Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease

Flanagan, Sarah E.; Haapaniemi, Emma; Russell, Mark A.; Caswell, Richard; Allen, Hana Lango; Franco, Elisa De; McDonald, Timothy J.; Rajala, Hanna; Ramelius, Anita; Barton, John; Heiskanen, Kaarina; Heiskanen‐Kosma, Tarja; Kajosaari, Merja; Murphy, Nuala; Milenković, Tatjana; Seppänen, Mikko; Lernmark, Åke; Mustjoki, Satu; Otonkoski, Timo; Kere, Juha; Morgan, Noel G.; Ellard, Sian; Hattersley, Andrew T.

doi:10.1038/ng.3040

Cited by 408 publications

(405 citation statements)

References 24 publications

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“…The basis for the small increased transcriptional activity and, presumably, the partial oncogenic capacity of STAT3C (as the mutant was named) was a more avid DNA binding of the STAT3C mutant leading to a slower off time from DNA than wild type and a concomitant slower dephosphorylation rate. Most recently human mutations, both positive-and negative-acting in STATs 1 and 3 (21,(27)(28)(29)(30)(31), have been reported especially in the SH2 domain, some of which have constitutive activity (31).…”

Section: Stat3 | Linker Domain | Mutantsmentioning

confidence: 99%

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Mertens

Haripal

Klinge

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Crystallography of the cores of phosphotyrosine-activated dimers of STAT1 (132–713) and STAT3 (127–722) bound to a similar double-stranded deoxyoligonucleotide established the domain structure of the STATs and the structural basis for activation through tyrosine phosphorylation and dimerization. We reported earlier that mutants in the linker domain of STAT1 that connect the DNA-binding domain and SH2 domain can prevent transcriptional activation. Because of the pervasive importance of persistently activated STAT3 in many human cancers and the difficulty of finding useful drug candidates aimed at disrupting the pY interchange in active STAT3 dimers, we have examined effects of an array of mutants in the STAT3 linker domain. We have found several STAT3 linker domain mutants to have profound effects of inhibiting STAT3 transcriptional activation. From these results, we propose (i) there is definite functional interaction of the linker both with the DNA binding domain and with the SH2 domain, and (ii) these putative contacts provide potential new targets for small molecule-induced pSTAT3 inhibition.

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Section: Stat3 | Linker Domain | Mutantsmentioning

confidence: 99%

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Mertens

Haripal

Klinge

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, activating STAT3 mutations may be not only associated with early-onset multi-organ autoimmune disease, but also with growth failure (68,69).…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

140

127

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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“…Rarely, a mutation in a single gene is the aetiological cause and the identification of the underlying monogenic defect can give important insights into mechanisms of beta-cell autoimmunity and pathways of immune tolerance (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Due to significant clinical overlap, discriminating patients with causative mutations in a single gene from those with a polygenic aetiology remains a challenge.…”

mentioning

confidence: 99%

“…Monogenic autoimmune disease often presents extremely early; for example, mutations in the STAT3, FOXP3 or IL2RA genes commonly present with neonatal diabetes (13,14,17). Mutations in LRBA typically presents with severe autoimmune disease early in childhood and diabetes is a feature in 22% of patients, however neonatal diabetes has not been confirmed (2).…”

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confidence: 99%

Recessively InheritedLRBAMutations Cause Autoimmunity Presenting as Neonatal Diabetes

et al. 2017

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Young-onset autoimmune diabetes associated with additional autoimmunity usually reflects a polygenic predisposition but rare cases result from monogenic autoimmunity. Diagnosing monogenic autoimmunity is crucial for patients' prognosis and clinical management. We sought to identify novel genetic causes of autoimmunity presenting with neonatal diabetes (NDM; diagnosis <6 months).We performed exome sequencing in a patient with NDM and autoimmune lymphoproliferative syndrome and his unrelated, unaffected parents and identified compound heterozygous null mutations in LRBA. Biallelic LRBA mutations cause Common Variable Immunodeficiency-8, however NDM has not been confirmed in this disorder.We sequenced LRBA in 169 additional

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Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease

Cited by 408 publications

References 24 publications

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Recessively InheritedLRBAMutations Cause Autoimmunity Presenting as Neonatal Diabetes

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