Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: A causative mutation? (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.
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.
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.
Frontiers in Neurology, 2018
Wide comprehension of genetic features of cerebral cavernous malformations (CCM) represents the starting point to better manage patients and risk rating in relatives. The causative mutations spectrum is constantly growing. KRIT1, CCM2, and PDCD10 are the three loci to date linked to familial CCM development, although germline mutations have also been detected in patients affected by sporadic forms. In this context, the main challenge is to draw up criteria to formulate genotype-phenotype correlations. Clearly, genetic factors determining incomplete penetrance of CCM need to be identified. Here, we report two novel intronic variants probably affecting splicing. Molecular screening of CCM genes was performed on DNA purified by peripheral blood. Coding exons and intron-exon boundaries were sequenced by the Sanger method. The first was detected in a sporadic patient and involves KRIT1. The second affects CCM2 and it is harbored by a woman with familial CCM. Interestingly, molecular analysis extended to both healthy and ill relatives allowed to estimate, for the first time, a penetrance for CCM2 lower than 100%, as to date reported. Moreover, heterogeneity of clinical manifestations among those affected carrying the same genotype further confirms involvement of modifier factors in CCM development.
A novel CCM1 mutation associated with multiple cerebral and vertebral cavernous malformations
BMC neurology, 2014
Cerebral cavernous malformations are relatively rare vascular disorders that may affect any part of the central nervous system. This presentation has been associated with heterozygous mutations in CCM1/KRIT1, CCM2/malcavernin and CCM3/PDCD10. We aimed to investigate the genetic defect underlying multiple cerebral and vertebral cavernous malformations in a multigenerational Italian family. The proband is a 49-year-old man who underwent cerebral MRI in his thirties for persistent haeadache and tingling in his left arm and leg and was diagnosed with multiple supratentorial cavernous angiomas. A right frontal angioma with radiological evidence of a recent bleeding was surgically removed when he was 39 years old and he was thereafter asymptomatic. Magnetic resonance imaging revealed multiple cerebral cavernous malformations in seven members of his familily. Four subjects were asymptomatic. Other family mambers displayed heterogeneous clinical features including seizures and recurrent bra...
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.
Journal of the Neurological Sciences, 2017
Cerebral cavernous malformations (CCMs) are clusters of capillaries in the brain that may cause focal deficits or seizures in affected patients. They occur in both sporadic and inherited autosomal dominant form. Germline mutations in CCM1, CCM2 and CCM3 were identified in familial cases. Over the past 13 years we performed sequencing and MLPA of the CCM genes in all sporadic and familial CCM cases coming from some hospital clinics of Neurology and Neurosurgery of Messina and other Italian cities. Our results showed that CCM sporadic patients, negative for previously reported CCM gene causative mutations, always carried known CCM polymorphisms. Previously, we reported polymorphisms in CCM2 gene associated with an increase in risk for CCM. Here, we undertook a case-control study to investigate the possible association of others polymorphisms (c.485 + 65 C/G, c.989 + 63 C/G, c.1980 A/G in CCM1 gene, c.472 + 127 C/T in CCM2 and c.150 G/A in CCM3) with CCMs. The five polymorphisms were characterized in 64 sporadic patients and in 90 healthy controls by ASO-PCR. Statistically significant differences in frequencies between patients and controls were found for c.485 + 65C/G, c.1980 A/G and c.472 + 127C/T polymorphisms. For c.485 + 65C/G polymorphism, a higher frequency of mutated allele (G) was found in patients group (9%) than in controls (2%) (p = 0.0041); for c.1980 A/G polymorphism, we found a frequency of mutated allele (G) higher in the control group (25%) compared to that of patients (8%) (p = 0.0396). Same trend was observed for c.472 + 127C/T polymorphism (T allele frequency = 34% and 6% in control group and patients, respectively; p = 0.0001). Polymorphisms c.485 + 65C/G, c.1980 A/G and c.472 + 127C/T were associated with an increased risk of CCM as indicated by odds ratio values. Furthermore, c.1980 A/G and c.472 + 127C/T polymorphisms were associated with less severe CCM symptomatology. Identification of these polymorphisms in CCM sporadic patient may represent a useful tool for clinicians to determine prognosis, scheduled periodic checks and appropriate treatment strategy.
Acta Neurologica Belgica, 2020
A 44-year-old female presented with an episodic left-sided throbbing headache associated with tearing of her left eye and occasional photophobia for the past 5 years. This headache was not associated with diplopia, drooping of her eyelids or redness of her eyes. Clinical examination was unremarkable. She had brain imaging to rule out any structural abnormality. The Magnetic resonance imaging (MRI) of the head with susceptibility-weighted imaging (SWI) sequences showed multiple cavernoma (more than 5), the largest of them being in the left inferior frontal and left occipital lobe (Fig. 1). Her father and his niece also experienced recurrent headache, and both were found to have multiple cavernoma in magnetic resonance imaging. However, her father's MRI scan revealed more infratentorial cavernoma than hers (Fig. 2). Her paternal grandfather died of intracerebral haemorrhage at the age of 60 years but had no genetic testing (not available that time). Her paternal grandfather's twin brother also passed away at a young age, but the exact cause remained unknown. Her genetic testing confirmed c.55c>T, p(Arg19*) mutation in the exon 2 of the cerebral cavernous malformation 2 (CCM2) gene (supplementary file). This gene change is predicted to result in premature termination of the CCM2 protein at arginine 19, p(Arg19*). Testing was done by bidirectional Sanger sequencing. Her son, father and father's