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Mutational analysis of 206 families with cavernous malformations
Maxwell S H Laurans1, Michael L DiLuna, Dana Shin
1Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Insights
A founder mutation in the KRIT1 gene is common in Hispanic individuals with cerebral cavernous malformation (CCM). This study identified various KRIT1 loss-of-function mutations, supporting a two-hit model for CCM development.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Cerebral cavernous malformation (CCM) is an autosomal-dominant neurological disorder.
- The KRIT1 (Krev Interaction Trapped 1) gene has been implicated in CCM pathogenesis.
Purpose of the Study:
- To characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene.
- To investigate the role of KRIT1 mutations in familial and sporadic CCM, particularly in Hispanic populations.
Main Methods:
- Collected blood samples from familial and sporadic CCM patients and their families.
- Utilized single-strand conformational polymorphism analysis and gene sequencing to identify KRIT1 variants.
- Performed linkage analysis to assess the role of the CCM1 locus.
Main Results:
- Identified a common founder mutation (Q455X) in the KRIT1 gene among Hispanic-American kindreds with CCM.
- This founder mutation was prevalent in both familial and apparently sporadic CCM cases within this population.
- Discovered 12 independent KRIT1 mutations in non-Hispanic CCM families, predominantly loss-of-function variants.
Conclusions:
- The findings highlight the significant role of a recent founder mutation in KRIT1 for CCM in Hispanic populations.
- All identified mutations were genetic loss-of-function types, including nonsense, frame-shift, and splice-site mutations.
- These genetic findings support a two-hit model for the development of cerebral cavernous malformation.
Object:
A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene.
Methods:
The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US. Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded.
Conclusions:
All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splice-site mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.