CCM2 – Cerebral Cavernous Malformation

Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system that predispose to seizures, focal neurological deficits, and hemorrhagic stroke. Familial CCMs are inherited in an autosomal dominant manner with incomplete penetrance and variable clinical expression. The CCM2 gene (MGC4607) encodes the adaptor protein malcavernin, which is essential for endothelial junction integrity and forms a ternary complex with KRIT1 and PDCD10.

Genetic studies have established a strong association between heterozygous loss-of-function mutations in CCM2 and autosomal dominant CCM. In a linkage and mutation screening study of 30 unrelated families, two distinct exon-deletion null alleles and eight point mutations (five nonsense, one frameshift, two splice-site) were identified in 10 families, all co-segregating with disease and absent in 192 control chromosomes (10 families)[PMID:14740320]. Subsequent case series and cohort screens have confirmed at least 67 additional CCM2 mutation carriers with vascular lesions and seizures across diverse populations ([PMID:17041941]).

The CCM2 variant spectrum includes frameshift deletions (e.g., c.502_503delAG (p.Leu169ValfsTer?)), nonsense changes, splice-site defects, and rare missense alterations. Notably, six PTB-domain missense variants (e.g., c.365T>G (p.Leu122Arg)) abolish CCM1–CCM2 interaction in co-immunoprecipitation assays, confirming their pathogenicity ([PMID:31937560]).

Functional assays demonstrate that CCM2 loss leads to failure of the CCM1/CCM2/CCM3 complex assembly, endothelial junction breakdown, and increased permeability. Structural and mutagenesis studies reveal that CCM2’s PTB domain binds KRIT1 NPXY motifs and that disruption of this interface causes loss of complex formation and proteasomal degradation of CCM proteins ([PMID:18300272]; [PMID:25825518]).

Although most CCM2 mutation carriers present with multiple CCM lesions and seizures (HP:0001250) or headaches (HP:0002315), expressivity is highly variable. Imaging-guided genetic testing enables early detection of asymptomatic carriers for surveillance and lesion removal before hemorrhage.

Overall, the evidence supports a Strong clinical validity classification for the CCM2–CCM relationship. Genetic and functional data are concordant and diagnostic testing of CCM2 is clinically actionable.

Key Take-home: Germline CCM2 mutations cause autosomal dominant cerebral cavernous malformation with strong genotype–phenotype correlation, supporting CCM2 sequencing in suspected familial cases.

References

• American Journal of Human Genetics • 2004 • Mutations within the MGC4607 gene cause cerebral cavernous malformations. PMID:14740320
• Human Mutation • 2008 • Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex. PMID:18300272
• The Journal of Cell Biology • 2015 • CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation. PMID:25825518

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