KRIT1 – Familial Cerebral Cavernous Malformations

Familial cerebral cavernous malformations (FCCM) is an autosomal dominant vascular disorder characterized by dilated capillary cavities in the central nervous system, predisposing to seizures, focal neurological deficits, and hemorrhagic stroke. Linkage analysis mapped CCM1 to chromosome 7q and identified KRIT1 as the causative gene, with truncating founder mutations (e.g., c.742C>T (p.Gln248Ter)) in Hispanic-American families and novel loss-of-function variants in Caucasian pedigrees (PMID:10807272).

Multiple case reports have since described private truncating mutations segregating with disease. A Chinese family with a novel exon 19 stop-gain, c.2092C>T (p.Gln698Ter), exhibited variable onset of seizures, ataxia, headaches and cutaneous vascular lesions across three generations (PMID:11959162). An Italian pedigree harboring a branch-point splice variant, c.1147-13C>G, likewise manifested migraine and epilepsy in affected members (PMID:12810002).

In a cohort of 140 FCCM individuals undergoing systematic molecular screening, heterozygous deleterious KRIT1 variants accounted for ~52% of mutations, with high concordance between ACMG classification and clinical phenotype (PMID:31254430). A larger study of 393 genotyped cases reported that 93% of pathogenic alleles were in KRIT1—predominantly the common Hispanic founder and additional private truncations—underscoring KRIT1’s predominance in FCCM genetics (PMID:34389651). Radiologic analysis of 34 FCCM patients further showed earlier and more severe lesion burden in KRIT1 mutation carriers (PMID:36629374).

Segregation analysis across five unrelated pedigrees (including father–child and sibling pairs in the facial paralysis case) confirmed autosomal dominant inheritance with incomplete penetrance in at least six additional affected relatives carrying truncating mutations (PMID:24156886).

Functional studies support a loss-of-function mechanism. KRIT1 protein fails to bind ICAP1α when NPXY motifs are disrupted, perturbing β1 integrin signaling in endothelial cells (PMID:11741838). Structural biology resolved the KRIT1 FERM domain in complex with Rap1 and HEG1, clarifying membrane recruitment and demonstrating that KRIT1 haploinsufficiency disrupts scaffold formation critical for vascular integrity (PMID:23814056).

Integration of genetic, segregation, and experimental data over >20 years establishes KRIT1 as a definitive FCCM gene. KRIT1 testing is recommended for clinical diagnosis, familial risk assessment, and therapeutic development targeting integrin–Rap1–HEG1 pathways.

Key Take-home: Autosomal dominant KRIT1 haploinsufficiency causes familial cerebral cavernous malformations; genetic testing informs diagnosis and family management.

References

• Journal of the neurological sciences • 2002 • Cerebral cavernous malformation: novel mutation in a Chinese family and evidence for heterogeneity. PMID:11959162
• Neurosurgery • 2000 • Mutations in KRIT1 in familial cerebral cavernous malformations. PMID:10807272
• Human mutation • 2019 • Molecular diagnostic workflow, clinical interpretation of sequence variants, and data repository procedures in 140 individuals with familial cerebral cavernous malformations. PMID:31254430
• Neurology • 2021 • Seizure Incidence Rates in Children and Adults With Familial Cerebral Cavernous Malformations. PMID:34389651
• 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
• The Journal of biological chemistry • 2013 • The structure of the ternary complex of Krev interaction trapped 1 (KRIT1) bound to both the Rap1 GTPase and the heart of glass (HEG1) cytoplasmic tail. PMID:23814056

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