Gain-of-function STAT1 mutations are associated with intracranial aneurysms.
Chronic mucocutaneous candidiasis, characterized by persistent or recurrent fungal infections, represents the clinical hallmark in gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) mutation carriers. Several cases of intracranial aneurysms have been reported in patients with GOF STAT1 mutation but the paucity of reported cases likely suggested this association still as serendipity. In order to endorse this association, we link the development of intracranial aneurysms with STAT1 GOF mutation by presenting the two different cases of a patient and her mother, and demonstrate upregulated phosphorylated STAT4 and IL-12 receptor β1 upon stimulation in patient's blood cells. We also detected increased transforming growth factor (TGF)-β type 2 receptor expression, particularly in CD14+cells, and a slightly higher phosphorylation rate of SMAD3. In addition, the mother of the patient developed disseminated bacille Calmette-Guérin disease after vaccination, speculating that GOF STAT1 mutations may confer a predisposition to weakly virulent mycobacteria.
Department of Neuroradiology, Hannover Medical School, Hannover, Germany.
Mete
M
Dadak
Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
Roland
R
Jacobs
Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Germany.
Jelena
J
Skuljec
Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Germany.
Adan Chari
AC
Jirmo
Department of Neurology, Hannover Medical School, Hannover, Germany.
Özlem
Ö
Yildiz
Department of Neuroradiology, Hannover Medical School, Hannover, Germany.
Frank
F
Donnerstag
Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
Niklas Thomas
NT
Baerlecken
Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
Reinhold Ernst
RE
Schmidt
Department of Neuroradiology, Hannover Medical School, Hannover, Germany.
Heinrich
H
Lanfermann
Department of Neurology, Hannover Medical School, Hannover, Germany.
Thomas
T
Skripuletz
Department of Neurology, Hannover Medical School, Hannover, Germany.
Philipp
P
Schwenkenbecher
Department of Neurology, University Clinic Essen, Essen, Germany.
Christoph
C
Kleinschnitz
Department of Neurology, University of Ulm, Ulm, Germany.
Hayrettin
H
Tumani
Department of Neurology, Hannover Medical School, Hannover, Germany.
Martin
M
Stangel
Department of Neurology, University Clinic Essen, Essen, Germany. Electronic address: refik.pul@uk-essen.de.
Refik
R
Pul
D000276:Adjuvants, Immunologic / Q000009:adverse effects; D000328:Adult; D015901:Angiography, Digital Subtraction; D001500:BCG Vaccine / Q000009:adverse effects; D002178:Candidiasis, Chronic Mucocutaneous / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002533:Cerebral Angiography; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D009035:Mothers; D009154:Mutation; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D053707:Receptors, Interleukin-12 / Q000276:immunology / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics*; D050797:STAT4 Transcription Factor / Q000276:immunology / Q000378:metabolism; D051900:Smad3 Protein / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000139:chemically induced / Q000276:immunology; D055815:Young Adult
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; C508438:IL12RB1 protein, human; D010750:Phosphoproteins; D053707:Receptors, Interleukin-12; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D051900:Smad3 Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
Aneurysm; Chronic mucocutaneous candidiasis; Gain-of-function mutation; Mendelian susceptibility to mycobacterial disease; SMAD3; STAT1; STAT4; Transforming growth factor-β