KRIT1 – Cerebral Cavernous Malformation

Familial cerebral cavernous malformation (CCM) is an autosomal-dominant vascular disorder characterized by clusters of dilated capillary cavities in the central nervous system. Positional cloning mapped the CCM1 locus to chromosome 7q21-22 and identified KRIT1 (HGNC:1573) as the disease gene, with seven different loss-of-function mutations in 23 distinct CCM1 families (PMID:10545614).

Genetic evidence for KRIT1-related CCM is robust: over 200 mutation carriers have been documented, including a recurrent founder splice-site mutation c.1146+1G>T and diverse truncating variants. A novel nonsense variant c.2092C>T (p.Gln698Ter) was reported in a Chinese family with five affected members presenting seizures, ataxia, headaches, and cutaneous lesions (PMID:11959162).

The variant spectrum is dominated by splice-donor, frameshift, and nonsense mutations (e.g., c.2092C>T (p.Gln698Ter)), leading to KRIT1 haploinsufficiency. No simple missense variants have been shown to be pathogenic without inducing aberrant splicing, supporting loss of function as the primary mechanism (PMID:11941540).

Segregation analyses across multiple pedigrees demonstrate co-segregation of KRIT1 truncating alleles with CCM phenotypes, albeit with incomplete clinical penetrance; at least 23 additional affected relatives have confirmed segregation of pathogenic KRIT1 variants (PMID:10545614).

Functional studies show that KRIT1 interacts with ICAP1α and the CCM2/CCM3 proteins to regulate integrin β1–mediated endothelial junction stability. Disruption of these interactions impairs endothelial barrier function and promotes lesion formation via a two-hit mechanism in vivo (PMID:11741838).

Integration of genetic and experimental data supports a definitive KRIT1–CCM1 association with CCM, informing presymptomatic testing, family screening, and tailored surveillance strategies. Key take-home: KRIT1 mutation analysis is essential for accurate diagnosis, risk assessment, and management of individuals with familial CCM.

References

• Human molecular genetics • 1999 • Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1) PMID:10545614
• Journal of the neurological sciences • 2002 • Cerebral cavernous malformation: novel mutation in a Chinese family and evidence for heterogeneity PMID:11959162
• American journal of human genetics • 2002 • Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation PMID:11941540
• Human molecular genetics • 2001 • Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation PMID:11741838

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