Flanagan SE et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.Nat Genet. 2014 Aug;46(8):812-4.
Monogenic autoimmunity syndromes are a rare cause of very early-onset multiple autoimmune manifestations. Flanagan et al report a new monogenic early-onset polyautoimmunity syndrome caused by activating STAT3 mutations. They initially used exome sequencing to identify an activating de novo germline STAT3 mutation in a patient presenting with extremely early-onset type 1 diabetes mellitus (2 weeks), hypothyroidism (3 years), and celiac disease (17 months); they then went on to identify four more patients with de novo STAT3 mutations by screening a cohort of patients with more than two early-onset autoimmune disorders and 39 patients with unexplained onset of permanent diabetes mellitus before 6 months. Other manifestations included autoimmune enteropathy and interstitial lung disease, juvenile-onset arthritis, hypothyroidism, eczema, and short stature.
The STAT (signal transducer and activator of transcription) factors are involved in early development, cell differentiation and proliferation. Interestingly, germline inactivating STAT3 mutations are associated with hyper-IgE syndrome, and somatic activating STAT3 mutations with large granular lymphocytic leukemia and inflammatory hepatocellular adenoma. Polymorphisms in STAT3 have been reported in association with autoimmune conditions other than those described here (Crohn’s disease, psoriasis, multiple sclerosis). The authors suggest that the mechanism of pathogenicity of activating STAT3 mutations is impaired regulatory T cell development and dysregulated proliferation and activation of helper T cells type 17.
Exome sequencing technology has the potential to expand our understanding of autoimmunity, both by identifying causes of rare monogenic disorders and by improving our understanding of the molecular pathophysiology of common diseases.
Posted by Alina Levtova, MD