Summary
Cerebral cavernous malformations (CCMs) are vascular disorders that affect up to 0.5% of the total population. About 20% of CCMs are inherited because of familial mutations in CCM genes, including
CCM1
/
KRIT1
,
CCM2
/
MGC4607
, and
CCM3
/
PDCD10
, whereas the etiology of a majority of simplex CCM-affected individuals remains unclear. Here, we report somatic mutations of
MAP3K3
,
PIK3CA
,
MAP2K7
, and CCM genes in CCM lesions. In particular, somatic hotspot mutations of
PIK3CA
are found in 11 of 38 individuals with CCMs, and a
MAP3K3
somatic mutation (c.1323C>G [p.Ile441Met]) is detected in 37.0% (34 of 92) of the simplex CCM-affected individuals. Strikingly, the
MAP3K3
c.1323C>G mutation presents in 95.7% (22 of 23) of the popcorn-like lesions but only 2.5% (1 of 40) of the subacute-bleeding or multifocal lesions that are predominantly attributed to mutations in the CCM1/2/3 signaling complex. Leveraging mini-bulk sequencing, we demonstrate the enrichment of
MAP3K3
c.1323C>G mutation in CCM endothelium. Mechanistically, beyond the activation of CCM1/2/3-inhibited ERK5 signaling, MEKK3 p.Ile441Met (
MAP3K3
encodes MEKK3) also activates ERK1/2, JNK, and p38 pathways because of mutation-induced MEKK3 kinase activity enhancement. Collectively, we identified several somatic activating mutations in CCM endothelium, and the
MAP3K3
c.1323C>G mutation defines a primary CCM subtype with distinct characteristics in signaling activation and magnetic resonance imaging appearance.
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