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Gain-of-function STAT1 mutations are associated with intracranial aneurysms

Mete Dadak1, Roland Jacobs2, Jelena Skuljec3

  • 1Department of Neuroradiology, Hannover Medical School, Hannover, Germany.

Clinical Immunology (Orlando, Fla.)
|February 6, 2017
PubMed

Insights

Gain-of-function signal transducer and activator of transcription 1 (STAT1) mutations are linked to intracranial aneurysms. These STAT1 mutations may also increase susceptibility to mycobacterial infections.

Area of Science:

  • Immunology
  • Genetics
  • Neurology

Background:

  • Gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) mutations typically cause chronic mucocutaneous candidiasis.
  • Intracranial aneurysms have been anecdotally reported in GOF STAT1 mutation carriers, but the association remains unclear.

Observation:

  • This study presents two cases linking intracranial aneurysms to GOF STAT1 mutations.
  • Upregulated phosphorylated STAT4 and IL-12 receptor β1 were observed in patient blood cells upon stimulation.
  • Increased transforming growth factor-β type 2 receptor expression and SMAD3 phosphorylation were detected in the patient.

Findings:

  • The study establishes a potential association between GOF STAT1 mutations and the development of intracranial aneurysms.
  • Elevated levels of specific signaling molecules (pSTAT4, IL-12Rβ1, TGF-β type 2 receptor, pSMAD3) suggest a molecular mechanism.
  • The patient's mother developed disseminated bacille Calmette-Guérin disease post-vaccination, indicating potential susceptibility to mycobacteria.

Implications:

  • This research highlights a potential neurological complication associated with GOF STAT1 mutations.
  • Understanding these molecular pathways may lead to novel therapeutic strategies for patients with STAT1 GOF mutations.
  • Further investigation is warranted to confirm the predisposition to mycobacterial infections in individuals with GOF STAT1 mutations.
Keywords:
AneurysmChronic mucocutaneous candidiasisGain-of-function mutationMendelian susceptibility to mycobacterial diseaseSMAD3STAT1STAT4Transforming growth factor-β

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