Mutation Analysis of <i>CCM1, CCM2</i> and <i>CCM3</i> Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation

D’Angelo, Rosalia; Marini, Valéria; Rinaldi, Carmela; Origone, Paola; Dorcaratto, Alessandra; Avolio, Maria; Gallelli, Luca; Forni, Marco; Capra, Valeria; Alafaci, Concetta; Mareni, Cristina; Garrè, Cecilia; Bramantı, Placido; Sidoti, Antonina; Retta, Saverio Francesco; Amato, Aldo

doi:10.1111/j.1750-3639.2010.00441.x

Cited by 54 publications

(27 citation statements)

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“…In the present study, a possible relationship between five known polymorphisms of CCM2 gene and sporadic CCMs was evaluated, starting from the ascertainment that in the cohort of patients, both sporadic and familial previously examined by us, only the sporadic patients showed these polymorphisms and were negative for CCM mutations (unpublished data) with the exception of two carrying two mutations in CCM2 gene (22).…”

Section: Discussionmentioning

confidence: 99%

“…As a result sometimes either mimicking a recessive trait in a given family or a sporadic condition in a family with an apparently negative history (21). In our recent study on mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation, both sporadic and familial, sixteen mutations were identified, and only two in sporadic patients (22).…”

Section: Introductionmentioning

confidence: 99%

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CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: A case-control study

et al. 2012

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Abstract. Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Among our group of CCM Italian patients, we selected a cohort of sporadic cases negative for mutations in CCM genes. In this cohort, five variants in CCM2 gene were detected, which proved to be the known polymorphisms in intronic regions (IVS2-36A>G and IVS8 +119 C>T) and in coding sequence (c.157 G>A in exon 2, c.358 G>A in exon 4 and c.915 G>A in exon 8). Therefore, we undertook a casecontrol study to investigate the possible association of these polymorphisms with sporadic CCMs. The five polymorphisms were identified in 91 CCM sporadic patients and in 100 healthy controls by direct sequencing methods using lymphocyte DNA. Polymorphisms IVS2-36A>G and c.915 G>A showed statistically significant differences in frequencies between patients and controls [(χ 2 , 6.583; P<0.037); (χ 2 , 14.205; P<0.001)]. The prevalence of the wild-type genotype was significantly lower in the CCM group than in the control sample. Patients with the A/G and G/G genotypes (IVS2-36A>G) had a significant increase for CCM risk (OR, 3.08; 95% CI, 1.5-5.9 and OR, 4.3; 95% CI, 1.4-22.6) and the same was observed for the polymorphism c.915 G> A (genotype G/A OR, 6.1; 95% CI, 3.0-12.6 and genotype A/A OR, 2.79). In addition, the polymorphisms c.358 G>A in exon 4 (χ 2 , 15.977; P<0.04) and c.915 G>A in exon 8 (χ 2 , 18.109; P<0.02) were significantly associated with different types of symptoms. Haplotype analysis, performed only on polymorphisms c.358 G>A (p.Val120Ile), c.915 G>A (p.Thr305 Thr) and IVS2-36A>G, shows that haplotype GAG (+--) significantly increased among CCM sporadic patients compared to the control group. Significant differences between patients and controls were observed only for IVS2-36A>G and c.915 G>A polymorphisms indicating their possible association with sporadic CCMs and an increased risk of CCM. On the other hand, polymorphisms c.358 G>A and c.915 G>A were associated with a more benign course of the disease. These data were confirmed by the haplotype GAG (+--) frequencies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: A case-control study

et al. 2012

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“…No CCM3 mutations were identified in another Italian cohort where, however, CCM1 mutation rate was equal to 1.3% [8]. …”

Section: Discussionmentioning

confidence: 99%

“…Causative mutations have been identified in three genes: CCM1 (K-Rev interaction trapped 1 (KRIT1)), CCM2 (MGC4607), and CCM3 (PDCD10) genes [8, 9], whose products, Krit1, malcavernin, and PDCD10, respectively, are involved in a common functional pathway.…”

Section: Introductionmentioning

confidence: 99%

Sporadic Cerebral Cavernous Malformations: Report of Further Mutations of CCM Genes in 40 Italian Patients

D’Angelo

Alafaci

Scimone

et al. 2013

BioMed Research International

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Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (K-Rev interaction trapped 1 (KRIT1)), CCM2 (MGC4607), and CCM3 (PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM.

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“…A couple of papers describe 122 and 79 CCM new patients, respectively (Riant et al, 2013;Spiegler et al, 2014), and expand the CCM mutation spectrum with a total of 74 novel variants. Two other works describe 16 and 19 additional Italian mutated patients (D'Angelo et al, 2011;Scimone et al, 2017), and highlight a possible high rate of CCM in Italy. However, population variability is covered only in part by such publications and interpretation of novel variants remains challenging for specific types of nucleotide change.…”

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A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

et al. 2018

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Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

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Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation

Cited by 54 publications

References 45 publications

CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: A case-control study

CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: A case-control study

Sporadic Cerebral Cavernous Malformations: Report of Further Mutations of CCM Genes in 40 Italian Patients

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

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