Cavernous angiomas of the nervous system in Italy: clinical and genetic study

Squitieri, Ferdinando; Maglione, Vittorio; Buzzi, Maria Gabriella; Nargi, E.; Novelletto, Andrea; Cannella, Milena; Simonelli, Maria; Colonnese, Claudio; Simonelli, P.; Innocenzi, Gualtiero; Gagliardi, F.; Caruso, Riccardo; G, Ragona; Cantore, Giampaolo

doi:10.1007/s100720070087

Cited by 10 publications

(7 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…All of these probands were positively diagnosed with CCMs by magnetic resonance imaging (MRI) and had multiple lesions and/or at least one other family member with a CCM lesion confirmed by MRI. These criteria have been used by us (Sahoo, et al, 1999;Liquori, et al, 2003) and others (Craig, et al, 1998;Squitieri, et al, 2000;Denier, et al, 2004;Bergametti, et al, 2005) as strong indicators of the inherited form of CCM. Significantly, sequence analysis of the CCM1 and CCM2 genes in these probands revealed no mutations.…”

Section: Resultsmentioning

confidence: 99%

Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus

et al. 2005

View full text Add to dashboard Cite

Cerebral cavernous malformations (CCMs) are vascular abnormalities of the brain that can result in a variety of neurological disabilities, including stroke and seizures. Linkage analyses using autosomal dominant families manifesting CCMs have identified three different causative loci on chromosomes 7q21.2 (CCM1), 7p13 (CCM2), and 3q25.2-q27 (CCM3). Mutations in the gene Krit1 are responsible for CCM1, mutations in the gene MGC4607 are responsible for CCM2, and mutations in the gene PDCD10 were recently reported to be responsible for CCM3. We report here that sequence analysis of PDCD10 in a panel of 29 probands lacking Krit1 and MGC4607 mutations revealed only three mutations. The frequency of identified mutations in the PDCD10 gene was surprisingly low, especially given that this panel was heavily biased towards non-CCM1, non-CCM2 probands. These data are in stark contrast with the linkage data, which suggests that 40% of inherited cases would be due to mutations in this gene. Interestingly, when examining the haplotypes of previously published CCM3 families, we found a distinct recombination event in one of the largest CCM3 families that excludes the PDCD10 gene. Although there are many potential explanations for this observation, when combined with the apparent underrepresentation of causative CCM mutations in PDCD10, this recombination event in a CCM3-linked family suggests that there may be an additional CCM gene in the same chromosomal region.

show abstract

Section: Resultsmentioning

confidence: 99%

Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Four of the families harboring MGC4607 mutations were previously reported as consistent with showing linkage to CCM2 (Craig et al 1998;Squitieri et al 2000;Dupre et al 2003). The remaining five families with…”

Section: Figurementioning

confidence: 86%

Mutations in a Gene Encoding a Novel Protein Containing a Phosphotyrosine-Binding Domain Cause Type 2 Cerebral Cavernous Malformations

Liquori

Berg

Siegel

et al. 2003

The American Journal of Human Genetics

310

219

View full text Add to dashboard Cite

Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. Mutations in the gene KRIT1 are responsible for type 1 CCM (CCM1). We report that a novel gene, MGC4607, exhibits eight different mutations in nine families with type 2 CCM (CCM2). MGC4607, similar to the KRIT1 binding partner ICAP1alpha, encodes a protein with a phosphotyrosine-binding domain. This protein may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation.

show abstract

“…Three gene loci have already been described, and a fourth locus was recently suspected [Liquori et al, 2006; Plummer et al, 2005]. Although virtually all cases of inherited CCM1 among the Hispanic population of Mexican descent in the United States arise from a founder mutation [Gunel et al, 1996], various CCM1 gene mutations have been reported in the Italian population [Laberge‐le Couteulx et al, 1999; Squitieri et al, 2000; Marini et al, 2003]. The genetic heterogeneity and penetrance variability [Denier et al, 2004] is complicated even further by evidence of Italian families carrying mutations in the other CCM genes, namely the CCM2 gene and a new, under‐study, CCM‐locus [Liquori et al, 2003, 2006].…”

Section: Clinical and Genetic Screening Of Italian Ccm Familiesmentioning

confidence: 99%

“…The genetic heterogeneity and penetrance variability [Denier et al, 2004] is complicated even further by evidence of Italian families carrying mutations in the other CCM genes, namely the CCM2 gene and a new, under‐study, CCM‐locus [Liquori et al, 2003, 2006]. We have set up a clinical and genomic data bank for Italian families with CCMs [Squitieri et al, 2000] and have undertaken comprehensive genetic screening of CCM genes (Table I). Data obtained from the genetic screening highlighted the presence of novel, as yet undescribed mutations, in CCM1 and CCM2 loci in two families, whereas complete sequencing of the CCM3 gene locus detected no mutations in our families.…”

Section: Clinical and Genetic Screening Of Italian Ccm Familiesmentioning

confidence: 99%

Highly variable penetrance in subjects affected with cavernous cerebral angiomas (CCM) carrying novel CCM1 and CCM2 mutations

Gianfrancesco

Cannella

Martino

et al. 2007

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Cavernous vascular malformations may affect brain and out-of-brain tissues. In most cases, cerebral cavernous malformations (CCMs) involve the brain alone, and are rarely associated with skin hemangiomas, spinal cord, retinal, hepatic or vertebral lesions. CCMs can cause seizures, intracranial and spinal haemorrhages, focal neurological deficits, and migraine-like headaches. After collecting CCM families of Italian origin and investigating the genetic basis of the disorder we disclosed two novel molecular variations in the KRIT1 and MGC4607 genes. We found a novel CCM1 gene mutation (Q66X) in a family with apparently asymptomatic old-aged mutation carriers and patients who either had skin angiomas alone or the full association of cerebral, spinal, and skin lesions. In this family we report the highest variability in mutation penetrance so far described, including the presence of CCM in one subject since birth (surgery at 19 months of age), a condition to our knowledge so far unreported. In a CCM2 affected family, we also report a novel causative mutation, (54_55delAC) in exon 2 of the MGC4607 gene, that produces a truncated protein containing only 22 amino acids. These data describe novel CCM mutations associated with a particularly high variability of the penetrance causing, in some cases, reduced expression of clinical symptoms and sporadic cases with apparent negative family history. Hence they emphasize the importance of DNA-based diagnostics and genetic counseling to identify unaffected mutation carriers subjects, even at advanced age.

show abstract

Cavernous angiomas of the nervous system in Italy: clinical and genetic study

Cited by 10 publications

References 17 publications

Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus

Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus

Mutations in a Gene Encoding a Novel Protein Containing a Phosphotyrosine-Binding Domain Cause Type 2 Cerebral Cavernous Malformations

Highly variable penetrance in subjects affected with cavernous cerebral angiomas (CCM) carrying novel CCM1 and CCM2 mutations

Contact Info

Product

Resources

About