Background

Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.

Objective

We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.

Methods

We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.

Results

We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.

Conclusions

Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.

The Research Centers in Minority Institutions (RCMI) program was established by the US Congress to support the development of biomedical research infrastructure at minority-serving institutions granting doctoral degrees in the health professions or in a health-related science. RCMI institutions also conduct research on diseases that disproportionately affect racial and ethnic minorities (ie, African Americans/Blacks, American Indians and Alaska Natives, Hispanics, Native Hawaiians and Other Pacific Islanders), those of low socioeconomic status, and rural persons. Quantitative metrics, including the numbers of doctoral science degrees granted to underrepresented students, NIH peer-reviewed research funding, peer-reviewed publications, and numbers of racial and ethnic minorities participating in sponsored research, demonstrate that RCMI grantee institutions have made substantial progress toward the intent of the Congressional legislation, as well as the NIH/NIMHD-linked goals of addressing workforce diversity and health disparities. Despite this progress, nationally, many challenges remain, including persistent disparities in research and career development awards to minority investigators. The continuing underrepresentation of minority investigators in NIH-sponsored research across multiple disease areas is of concern, in the face of unrelenting national health inequities. With the collaborative network support by the RCMI Translational Research Network (RTRN), the RCMI community is uniquely positioned to address these challenges through its community engagement and strategic partnerships with non-RCMI institutions. Funding agencies can play an important role by incentivizing such collaborations, and incorporating metrics for research funding that address underrepresented populations, workforce diversity and health equity.