Simplex cerebral cavernous malformations with MAP3K3 mutation have distinct clinical characteristics

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• Cerebral cavernous malformations (CCMs) are vascular anomalies with a risk of hemorrhage.
• Somatic mutations in CCM genes (e.g., CCM2) are established causes of CCMs.
• The role of MAP3K3 somatic mutations in CCM pathogenesis and clinical presentation requires further elucidation.

Purpose of the Study:

• To investigate the clinical characteristics of simplex cerebral cavernous malformations (CCMs) associated with MAP3K3 somatic mutations.
• To compare the hemorrhage risk between CCMs with MAP3K3 mutations and those with canonical CCM gene mutations.
• To explore the underlying molecular mechanisms by which MAP3K3 mutations influence CCMs.

Main Methods:

• Retrospective review of a CCM database (May 2017-December 2019) including patients with simplex CCMs and MAP3K3 or CCM gene somatic mutations.
• Univariate and multivariate logistic analyses to identify risk factors for hemorrhage.
• In vitro studies using human umbilical vein endothelial cells (HUVECs) transfected with MEKK3-I441M (MAP3K3 mutant) or CCM2-knockdown lentiviruses.
• Western blotting, immunofluorescence, and immunohistochemistry to assess protein expression (e.g., thrombomodulin, ZO-1) and pathway activation (NF-κB).

Main Results:

• Fifty simplex CCM patients were analyzed (38 with MAP3K3 mutations, 12 with CCM gene mutations).
• Hemorrhage incidence was significantly lower in MAP3K3-mutant CCMs (23.7%) compared to CCM gene-mutant CCMs (91.7%).
• MAP3K3 mutations were associated with lower hemorrhage risk. In vitro, MAP3K3 mutations increased thrombomodulin expression and activated NF-κB signaling, while CCM2 knockdown decreased tight junction protein ZO-1 expression.

Conclusions:

• Simplex CCMs with MAP3K3 mutations exhibit distinct clinical characteristics, notably a reduced risk of overt hemorrhage.
• The biological function of MAP3K3 mutations influences CCM presentation, potentially through modulation of thrombomodulin and tight junction integrity.
• Further research into the specific molecular pathways affected by MAP3K3 mutations is warranted to understand CCM pathogenesis.