A novel syndrome of cerebral cavernous malformation and Greig cephalopolysyndactyly (original) (raw)
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BioMed Research International, 2013
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.
CCM1 gene mutations in families segregating cerebral cavernous malformations
Neurology, 2001
CCM1 gene mutations in families segregating cerebral cavernous malformations Article abstract-Cerebral cavernous malformations (CCM) are vascular anomalies, sometimes inherited as an autosomal dominant trait, which can cause strokes and seizures. Recently, mutations of the CCM1 gene (chromosome 7q) have been found in a subset of families. The authors found 10 new mutations by screening 29 families and five seemingly sporadic cases of CCM. The mutations predicted truncation of the Krit1 mRNA encoded by CCM1, supporting the contention that CCM result from loss of Krit1 protein function and the possibility that this protein acts as a tumor suppressor.
Molecular genetics of familial cerebral cavernous malformations
Neurosurgical Focus, 2006
✓Cerebral cavernous malformations (CMs) are angiographically occult neurovascular lesions that consist of enlarged vascular channels without intervening normal parenchyma. Cavernous malformations can occur as sporadic or auto-somal-dominant inherited conditions. Approximately 50% of Hispanic patients with cerebral CMs have the familial form, compared with 10 to 20% of Caucasian patients. There is no difference in the pathological findings or presentation in the sporadic and familial forms. To date, familial CMs have been attributed to mutations at three different loci: CCM1 on 7q21.2, CCM2 on 7p15-p13, or CCM3 on 3q25.2-q27. The authors summarize the current understanding of the molecular events underlying familial CMs.
Gene, 2013
24 mRNA decay 25 Haploinsufficiency 26 Two-hit model 27 Cerebral cavernous malformations (CCMs; OMIM 116860) are vascular anomalies mostly located in the 28 central nervous system (CNS) and occasionally within the skin and retina. 29 Main clinical manifestations are seizure, hemorrhage, recurrent headaches, focal neurological deficits and 30 epileptic attacks. The CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete 31 penetrance and variable clinical expression. 32 Familial CCMs were associated with causative mutations in the CCM1 [K-Rev interaction trapped 1 (KRIT1)], 33 CCM2 (MGC4607) and CCM3 (PDCD10) genes.
Archives of neurology, 2007
Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in seizures, hemorrhage, recurrent headaches, and focal neurologic deficits. These CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete penetrance and variable clinical expression. Three CCM loci have been identified, on chromosomes 7q21-22 (CCM1; Online Mendelian Inheritance in Man [OMIM] 116860), 7p13-15 (CCM2; OMIM 603284), and 3q25.2-27 (CCM3; OMIM 603285), and 3 genes have been cloned, KRIT1 on CCM1, MGC4607 on CCM2, and PDCD10 on CCM3. Mutations in KRIT1 account for more than 40% of CCMs. To describe the results of a comprehensive evaluation of 5 Italian families affected with CCM. Clinical, magnetic resonance imaging, and KRIT1 gene analysis. University academic teaching hospitals. Fifteen patients with CCM diagnosed according to defined criteria and 45 at-risk, symptom-free relatives. Three novel and 2 described mutations we...
Update on Novel CCM Gene Mutations in Patients with Cerebral Cavernous Malformations
Journal of Molecular Neuroscience, 2016
Cerebral cavernous malformations (CCMs) are lesions affecting brain microvessels. The pathogenesis is not clearly understood. Conventional classification criterion is based on genetics, and thus, familial and sporadic forms can be distinguished; however, classification of sporadic cases with multiple lesions still remains uncertain. To date, three CCM causative genes have been identified: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. In our previous mutation screening, performed in a cohort of 95 Italian patients, with both sporadic and familial cases, we identified several mutations in CCM genes. This study represents further molecular screening in a cohort of 19 Italian patients enrolled by us in the few last years and classified into familial, sporadic and sporadic with multiple lesions cases. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect point mutations and large genomic rearrangements, respectively. Effects of detected mutations and single-nucleotide polymorphisms (SNPs) were evaluated by an in silico approach and by western blot analysis. A novel nonsense mutation in CCM1 and a novel missense mutation in CCM2 were detected; moreover, several CCM2 gene polymorphisms in sporadic CCM patients were reported. We believe that these data enrich the mutation spectrum of CCM genes, which is useful for genetic counselling to identify both familial and sporadic CCM cases, as early as possible.
Molecular genetic analysis of cerebral cavernous malformations: an update
Vessel Plus, 2021
Cerebral cavernous malformations (CCM) can occur either as sporadic or familial form with autosomal dominant inheritance. Three CCM genes have been identified: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). In this review, we provide an overall update on genetics of cerebral cavernous malformations. We discuss the main features of these three genes and provide an updated listing of the mutations identified so far. Most of them lead to a premature stop codon regardless of the nature of the variation, including nonsense mutations, small deletions/insertions, and intronic/exonic substitutions causing an altered splicing and a frame-shift. In addition, deletions or duplications of one or more exons of CCM genes can be responsible for the disease. We examine the use of different mutation screening methods to identify all these mutations, providing a comprehensive approach to CCM genetic diagnosis. We also report the main strategies to evaluate the actual impact of the mutations on the protein function. Moreover, we recapitulate the available data on penetrance, phenotype-genotype correlations, and founder effect. Finally, we discuss the main aspects of genetic counseling, including genetic risk assessment in family members, in sporadic patients with multiple CCMs, and in the case of de novo mutations.
Genome Research, 1995
Cerebral cavernous malformations (CCM} are vascular lesions present in some 20 million people worldwide that are responsible for seizures, migraine, hemorrhage, and other neurologic problems. Familial cases of CCM can be inherited as an autosomal dominant disorder with variable expression. A gene for CCM (CCM/) was recently mapped to a 33-cM segment of chromosome 7q in a large Hispanic family (Dubovsky et al. 1995}. Here, the collection of several new short tandem repeat polymorphisms (STRPs) within the region of interest on 7q and the refinement of the marker order in this region using both linkage analysis in CEPH families and especially YAC-based STS content mapping are described. Affected members of three Hispanic families share allele haplotypes indicating a common ancestral mutation within these families. Using the shared haplotype information along with analysis of crossovers in affected individuals from both the Hispanic and Caucasian families, the region likely to contain the CCMI gene has been reduced to a 4-cM segment of 7q between D7S2410 and D7S689. All markers within the refined chromosomal segment were located on a single YAC contig estimated to be-2 Mb in size. Four potential candidate genes have been mapped to this region. Cerebral cavernous malformations (CCM) (also called cerebral cavernous angiomas or cavernous hemangiomas) are vascular malformations consisting of large, closely clustered enlarged capillary channels (caverns) with a single layer of en-17Corresponding author.
Cells
Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient’s life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a...