Somatic variants of MAP3K3 are sufficient to cause cerebral and spinal cord cavernous malformations

Document Type

Article

Publication Date

3-30-2023

Institution/Department

Neurology; MaineHealth Institute for Research

Journal Title

Brain : A Journal of Neurology

Abstract

Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the central nervous system that can lead to seizure, hemorrhage, and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analyzed whole-exome sequencing data for patients with CCM and found that ∼40% of them have a single, specific MAP3K3 mutation (c.1323C>G [p.Ile441Met]) but not any other known mutations in CCM-related genes. We developed a mouse model of CCM with MAP3K3I441M uniquely expressed in the endothelium of the central nervous system. We detected pathological phenotypes similar to those found in patients with MAP3K3I441M. The combination of in vivo imaging and genetic labeling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood-brain barrier. Experiments with our MAP3K3I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1/2/3 and/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs.

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