Familial Cerebral Cavernous Malformations

Zafar, Atif; Quadri, Syed A.; Farooqui, Mudassir; Agrebi, I.; Robinson, Myranda; Hart, Blaine L.; Mabray, Marc C.; Vigil, Catherine; Tang, Alan T.; Kahn, Mark L.; Yonas, Howard; Lawton, Michael T.; Kim, Helen; Morrison, Leslie

doi:10.1161/strokeaha.118.022314

Cited by 109 publications

(115 citation statements)

References 55 publications

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“…The current study identified a novel frameshift mutation in CCM1 (c.1635delA) in a Chinese family with CCMs. In this three-generation family with 20 family members, about 30% of them (six members) have developed CCMs with multiple lesions that are the common features of FCCMs (Zafar et al, 2019;Flemming and Lanzino, 2020). The positive family history in which CCMs are present in the proband, her maternal grandmother, her mother, and her uncles indicated an autosomal dominant inheritance.…”

Section: Discussionmentioning

confidence: 89%

“…As CCM1 plays a critical role in endothelial cell junctions of blood vessels, we speculated that this CCM1 mutation could be a causative factor for CCMs in the Chinese family. Gene variants of FCCMs are found in three genes, CCM1, CCM2, and CCM3 (Morrison andAkers, 2003 [updated 2016 Aug 4]; Spiegler et al, 2018;Zafar et al, 2019). To date, more than 200 germline genetic variants in CCM1-3 have been unraveled as causative factors for the etiology of CCMs (Scimone et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…As the second most prevalent vascular malformations in the central nervous system, CCMs account for 10-15% of all vascular malefactions cases (Batra et al, 2009;Flemming et al, 2017). The majority of CCMs are sporadic, covering over 90% of all cases while familial CCMs (FCCMs) only account for 6-7%, which is considered as a rare disease (Moriarity et al, 1999a;Batra et al, 2009;Spiegler et al, 2018;Zafar et al, 2019). However, less than 20% of patients with sporadic CCMs have multiple lesions (Moriarity et al, 1999b;Dammann et al, 2017;Flemming and Lanzino, 2020), whereas over 50% of FCCMs cause multiple CCM lesions, which will increase the risk of developing epilepsy and intracranial hemorrhage (Russo et al, 2017;Zafar et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…FCCMs are inherited in an autosomal dominant manner with incomplete penetrance. The specific pathogenic genes of FCCMs mainly include CCM1/KRIT1 (Krev1 interacting trapped gene), CCM2/MGC4607, and CCM3/PDCD10 (programmed cell death protein 10) (Dupre et al, 2003;Bergametti et al, 2005;Denier et al, 2006;Chang et al, 2019;Cianfruglia et al, 2019;Zafar et al, 2019). About 87-98% of patents with FCCMs have been found to carry mutations in one of these CCM genes (Denier et al, 2006;Spiegler et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Novel CCM1 Frameshift Mutation in a Chinese Han Family With Multiple Cerebral Cavernous Malformations

et al. 2020

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Cerebral cavernous malformations (CCMs) are vascular lesions that predominantly occur in the brain. CCMs can be sporadic or hereditary in an autosomal dominant manner. The genes harboring variants of familial CCMs (FCCMs) include CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. In this study, we identified a novel CCM1/KRIT1 mutation in a Chinese family with FCCMs. This family consists of 20 members, and 6 of them had been diagnosed with CCMs. The proband patient is a 17-year-old female who has suffered from CCM-related intracranial hemorrhage four times. Magnetic resonance imaging (MRI) revealed four lesions in the different brain regions and one lesion has progressively enlarged. The pathological histology confirmed CCMs. Whole exome sequencing revealed a novel deletion mutation (c.1635delA) within exon 15 of CCM1/KRIT1 gene in the proband patient, her mother, and her uncle who had CCMs. This frameshift mutation led to a premature termination codon (PTC) at nucleotides 1652-1654. We also detected that the CCM1 mRNA levels in the blood lymphocytes of the family members with CCMs were reduced by 46.4% compared to that in healthy controls. Collectively, our results suggested that the CCM1 mutation could potentially be a causative factor for FCCMs in the Chinese family and the reduction of CCM1 mRNA expression in the blood lymphocytes of the patients might be a potential biomarker for the diagnosis and prognosis of CCMs. Our findings expanded the spectrum of CCM mutations and helped to guide genetic counseling and early genetic diagnosis for at-risk family members.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of a Novel CCM1 Frameshift Mutation in a Chinese Han Family With Multiple Cerebral Cavernous Malformations

et al. 2020

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“…Of all familial CCM patients,~60% have CCM1 mutations,~20% have CCM2 mutations,~10% have CCM3 mutations, and a minority of familial CCM patients do not have mutations in these three genes [17]. Although mutations of KRIT1, CCM2, and PDCD10 genes are all associated with histologically identical CCM lesions, patients with PDCD10 mutations have the most severe phenotype, with earlier symptomatic onset [18,19].…”

Section: Genetics Of Ccmmentioning

confidence: 99%

Cerebral Cavernous Malformation Proteins in Barrier Maintenance and Regulation

Wei

Polster

et al. 2020

IJMS

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Cerebral cavernous malformation (CCM) is a disease characterized by mulberry shaped clusters of dilated microvessels, primarily in the central nervous system. Such lesions can cause seizures, headaches, and stroke from brain bleeding. Loss-of-function germline and somatic mutations of a group of genes, called CCM genes, have been attributed to disease pathogenesis. In this review, we discuss the impact of CCM gene encoded proteins on cellular signaling, barrier function of endothelium and epithelium, and their contribution to CCM and potentially other diseases.

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