Cerebral cavernous malformation: Clinical report of two families with variable phenotype associated with KRIT1 mutation

Balasubramanian, Meena; Jain, Vani; Glover, Rhona C.; Robertson, Laura; Mordekar, Santosh R.

doi:10.1016/j.ejpn.2013.05.003

European Journal of Paediatric Neurology

2013

DOI: 10.1016/j.ejpn.2013.05.003

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Cerebral cavernous malformation: Clinical report of two families with variable phenotype associated with KRIT1 mutation

Meena Balasubramanian

Vani Jain

Rhona C. Glover

et al.

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Cited by 3 publications

References 16 publications

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Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population

Yang¹,

Zhao²,

Wu³

et al. 2016

J Mol Neurosci

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Cerebral cavernous malformation (CCM) is a congenital vascular anomaly predominantly located within the central nervous system. Its familial forms (familial cerebral cavernous malformation (FCCM)), inherited in an autosomal dominant manner with incomplete penetrance, are attributed to mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes. To date, little is known about the genetic alterations leading to FCCM in the Chinese population. We aimed to investigate the genetic defect of FCCM by DNA sequencing in Chinese families. This study enrolled five Chinese families with FCCM. All index cases underwent surgical treatment and were diagnosed with CCM by pathology; their relatives were diagnosed based on radiological and/or pathological evidence. Genomic DNA was extracted from peripheral blood and amplified using polymerase chain reaction (PCR) for DNA sequencing. The five families comprised a total of 21 affected individuals: 12 of these were symptomatic, and 9 were asymptomatic. Sequence analyses in the index patients disclosed three heterozygous loss-of-function mutations in the CCM1/KRIT1 gene in three families, respectively: a novel deletion mutation (c.1780delG; p.Ala594HisfsX67) in exon 16, a novel splice-site mutation (c.1412-1G>A) in the splice acceptor site in intron 13, and a previously described 4-bp deletion (c.1197_1200delCAAA; p.Gln401ThrfsX10) in exon 12. All of these mutations are predicted to cause a premature termination codon to generate a truncated Krev interaction trapped 1 (Krit1) protein. These mutations segregated in affected relatives. Our findings provided new CCM1 gene mutation profiles, which help to elucidate the pathogenesis of FCCM and will be of great significance in genetic counseling.

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Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population

Yang¹,

Zhao²,

Wu³

et al. 2016

J Mol Neurosci

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A Novel CCM1/KRIT1 Heterozygous Nonsense Mutation (c.1864C>T) Associated with Familial Cerebral Cavernous Malformation: a Genetic Insight from an 8-Year Continuous Observational Study

et al. 2017

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Cerebral cavernous malformation (CCM) is a congenital vascular abnormality that predominantly affects the central nervous system, but that sometimes encroaches other vital tissues, including the retina, skin, and even liver. The familial form of CCM (FCCM) is considered to be an autosomal dominant disease with incomplete penetrance and variable expression, which is often attributed to mutations in three genes: CCM1, CCM2, and CCM3. We screened a Chinese family diagnosed with FCCM by using Sanger sequencing. A 29-year-old male proband with cutaneous angiomas was pathologically diagnosed but presented with an atypical form of CCM as revealed by magnetic resonance imaging (MRI) findings, prompting further clinical evaluation and genetic analyses of him and his immediate family. We performed continuous observation over an 8-year period using MRI gradient echo imaging and susceptibility-weighted imaging of these individuals. Sanger sequencing of the CCM1, CCM2, and CCM3 genes identified a novel heterozygous nonsense nucleotide transition (c.1864C>T; p.Gln622X) in exon 17 of the CCM1/KRIT1 gene; this mutation was predicted to cause a premature stop codon (TAG) at nucleotides 1864 to 1866 to generate a truncated Krev interaction trapped 1 (Krit1) protein of 621 amino acids. During this long-term observational study, one of the enrolled family members with neurological deficits progressed to a stage indicative of brain surgery. This study provides a new CCM gene mutation profile, which highlights the significance of genetic counseling for individuals suspected of having this condition.

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Status epilepsy in CCM with KRIT1 gene change

Craft

Vasudevan²

2014

European Journal of Paediatric Neurology

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Cerebral cavernous malformation: Clinical report of two families with variable phenotype associated with KRIT1 mutation

Cited by 3 publications

References 16 publications

Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population

Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population

A Novel CCM1/KRIT1 Heterozygous Nonsense Mutation (c.1864C>T) Associated with Familial Cerebral Cavernous Malformation: a Genetic Insight from an 8-Year Continuous Observational Study

Status epilepsy in CCM with KRIT1 gene change

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