Exome sequencing reveals gain-of-function mutations in STAT1 conferring predisposition to chronic mucocutaneous candidiasis and tuberculosis in six Colombian patients

Marcela Moncada-Vélez, Lucía Victoria Erazo-Borrás, Jesús Armando Álvarez-lvarez, Carlos Andrés Arango, Miyuki Tsumura, Satoshi Okada, Sara Daniela Osorio, Lorena Castro, Natalia González, Catalina Arango, Julio César Orrego, Lina Riaño, Juan Fernando Alzate, Felipe Cabarcas, Jean-Laurent Casanova, Jacinta Bustamante, Anne Puel, Andrés Augusto Arias, José Luis Franco


Background: The transcription factor STAT1 plays a critical role in the immune response against mycobacterial, viral and fungal infections. Different mutations in STAT1 result in diverse clinical phenotypes: AR complete/partial biallelic mutations are associated with mycobacterial and viral infections while AD loss-of-function (LOF) mutations with mycobacterial disease only; in addition, AD gain-of-function (GOF) mutations are associated with autoimmunity and fungal infections. We now report novel mutations in STAT1 in six individuals from a large cohort of Colombians affected with mycobacterial, fungal and bacterial infectious diseases.

Methods: We performed whole exome sequencing (WES) in four sporadic cases (P1, P2, P3 and P4) and the proband of one family case (P5). We confirmed mutations via Sanger sequencing in patients and family members. To assess the functional impact, we evaluated the STAT1 phosphorylation after stimulation with IFN-gamma in patients’ PBMC by flow cytometry and using the in vitro dual-glo luciferase assay.

Results: Infections in the patients included chronic mucocutaneous candidiasis and pulmonary histoplasmosis in P1, chronic mucocutaneous candidiasis and pulmonary tuberculosis in P2, and chronic mucocutaneous candidiasis in P3, P4, P5 and P6. We found three novel (Q20R, E235G and L354R) and one previously reported (C324Y), heterozygous missense mutations in STAT1 in four sporadic cases (P1, P3, P2 and P4, respectively) and the previously reported P329L mutation in P5 and her father (P6). The novel mutations are predicted to be deleterious by SIFT and polyphen2. Patients’ PBMCs and the GAS reporter assay showed higher phosphorylation of STAT1 in response to IFN-gamma stimulation demonstrating that all mutant alleles were GOF.

Conclusions: GOF-STAT1 mutations in our patients lead to a spectrum of chronic mucocutaneous candidiasis, histoplasmosis and tuberculosis, therefore STAT1 investigation should be addressed in patients with these types of infectious diseases. In addition, WES has become an important tool in the identification of genetic defects in patients with PID.

Palabras clave

Mutations in STAT1; Whole exome sequencing; Chronic mucocutaneous candidiasis; Tuberculosis

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