Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation

Area of Science:

• Vascular biology
• Genetics
• Neuroscience

Background:

• Cerebral cavernous malformations (CCMs) are vascular anomalies affecting up to 0.5% of the population.
• While 20% of CCMs have inherited causes due to mutations in CCM1/KRIT1, CCM2/MGC4607, or CCM3/PDCD10, the origins of most sporadic cases remain unknown.
• Understanding the genetic basis of CCMs is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the genetic underpinnings of sporadic cerebral cavernous malformations.
• To identify specific somatic mutations within CCM lesions.
• To characterize the molecular mechanisms and clinical associations of identified mutations.

Main Methods:

• Somatic mutation analysis of CCM lesions from affected individuals.
• Mini-bulk sequencing to determine mutation enrichment in specific cell types.
• Functional assays to assess the impact of mutations on signaling pathways.

Main Results:

• Somatic mutations in MAP3K3, PIK3CA, MAP2K7, and CCM genes were identified in CCM lesions.
• Somatic hotspot mutations in PIK3CA were found in 11 of 38 individuals.
• A specific MAP3K3 somatic mutation (c.1323C>G [p.Ile441Met]) was detected in 37% of sporadic CCM cases and strongly associated with popcorn-like lesions.
• This MAP3K3 mutation was enriched in CCM endothelium and activated multiple signaling pathways (ERK1/2, JNK, p38) beyond the canonical CCM pathway.

Conclusions:

• Several somatic activating mutations occur in the endothelium of CCM lesions.
• The MAP3K3 c.1323C>G mutation represents a primary CCM subtype with distinct signaling activation and MRI characteristics.
• This discovery offers new insights into CCM pathogenesis and potential diagnostic markers.