Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: A causative mutation?

D’Angelo, Rosalia; Scimone, Concetta; Calabrò, Marco; Schettino, Carla; Fratta, Mario; Sidoti, Antonina

doi:10.1016/j.gene.2012.09.045

Cited by 12 publications

(5 citation statements)

References 24 publications

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“…CCMs may be both sporadic and familial. Some previous reports have described mutation of CCM genes in worldwide familial CCMs 4 5 6) . In this report, we describe one novel and one known mutation of the CCM1 gene occurring in two, Korean family patients with CCMs with epilepsy.…”

Section: Discussionmentioning

confidence: 98%

Two cases of familial cerebral cavernous malformation caused by mutations in theCCM1gene

et al. 2016

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Cerebral cavernous malformation (CCM) is a vascular malformation characterized by abnormally enlarged capillary cavities without any intervening neural tissue. We report 2 cases of familial CCMs diagnosed with the CCM1 mutation by using a genetic assay. A 5-year-old boy presented with headache, vomiting, and seizure-like movements. Brain magnetic resonance imaging (MRI) revealed multiple CCM lesions in the cerebral hemispheres. Subsequent mutation analysis of his father and other family members revealed c.940_943 del (p.Val314 Asn315delinsThrfsX3) mutations of the CCM1 gene. A 10-month-old boy who presented with seizure-like movements was reported to have had no perinatal event. His aunt was diagnosed with cerebral angioma. Brain and spine MRI revealed multiple angiomas in the cerebral hemisphere and thoracic spinal cord. Mutation analysis of his father was normal, although that of the patient and his mother revealed c.535C>T (p.Arg179X) mutations of the CCM1 gene. Based on these studies, we suggest that when a child with a familial history of CCMs exhibits neurological symptoms, the physician should suspect familial CCMs and consider brain imaging or a genetic assay.

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Section: Discussionmentioning

confidence: 98%

Two cases of familial cerebral cavernous malformation caused by mutations in theCCM1gene

et al. 2016

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“…RNA surveillance mechanisms such as the NMD pathway are increasingly recognized as important in nervous system development and function, synaptic plasticity and neurological diseases including certain epilepsies 19 20 21 22 23 . The present study found that status epilepticus produces changes to hippocampal levels of NMD proteins, including levels of Upf1, which is required for formation of mRNA surveillance complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Nonsense mutations have been described in γ-amino butyric acid (GABA) receptors and synaptic proteins which have been implicated in the human epilepsies and experimentally verified to be targeted by the NMD system 19 20 21 22 23 . Whether the NMD system is involved in the pathophysiologic changes associated with the development of epilepsy – epileptogenesis - has not been investigated.…”

mentioning

confidence: 99%

RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis

Mooney

Jiménez-Mateos

Engel

et al. 2017

Sci Rep

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The nonsense mediated decay (NMD) pathway is a critical surveillance mechanism for identifying aberrant mRNA transcripts. It is unknown, however, whether the NMD system is affected by seizures in vivo and whether changes confer beneficial or maladaptive responses that influence long-term outcomes such the network alterations that produce spontaneous recurrent seizures. Here we explored the responses of the NMD pathway to prolonged seizures (status epilepticus) and investigated the effects of NMD inhibition on epilepsy in mice. Status epilepticus led to increased protein levels of Up-frameshift suppressor 1 homolog (Upf1) within the mouse hippocampus. Upf1 protein levels were also higher in resected hippocampus from patients with intractable temporal lobe epilepsy. Immunoprecipitation of Upf1-bound RNA from the cytoplasmic and synaptosomal compartments followed by RNA sequencing identified unique populations of NMD-associated transcripts and altered levels after status epilepticus, including known substrates such as Arc as well as novel targets including Inhba and Npas4. Finally, long-term video-EEG recordings determined that pharmacologic interference in the NMD pathway after status epilepticus reduced the later occurrence of spontaneous seizures in mice. These findings suggest compartment-specific recruitment and differential loading of transcripts by NMD pathway components may contribute to the process of epileptogenesis.

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“…Cerebral cavernous malformations (CCMs) are characterized by distended intracranial capillary cavities amidst a thin layer of endothelial cells (EC) that lack support of intervening parenchyma and predispose to intracranial hemorrhage [1,2]. Till date, the mutation in the three CCM genes, including KRIT1 ( CCM1 ) [3–7]; MGC4607/Malcavernin ( CCM2 ) [7–9]; and PDCD10 ( CCM3 ) [7,10] are identified as the main causes of CCMs. At least one of these genes is disrupted in most CCM cases in humans [2].…”

Section: Introductionmentioning

confidence: 99%

Novel functions of CCM1 delimit the relationship of PTB/PH domains

Zhang

Dubey

Padarti

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: A causative mutation?

Cited by 12 publications

References 24 publications

Two cases of familial cerebral cavernous malformation caused by mutations in theCCM1gene

Two cases of familial cerebral cavernous malformation caused by mutations in theCCM1gene

RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis

Novel functions of CCM1 delimit the relationship of PTB/PH domains

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