Journal of Molecular Neuroscience

, Volume 61, Issue 4, pp 511–523 | Cite as

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

  • Chenlong Yang
  • Van Halm-Lutterodt Nicholas
  • Jizong Zhao
  • Bingquan Wu
  • Haohao Zhong
  • Yan Li
  • Yulun Xu
Article

Abstract

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.

Keywords

Cerebral cavernous malformation Familial cerebral cavernous malformation CCM1/KRIT1 Novel mutation Nonsense mutation 

Notes

Acknowledgements

The authors thank the proband and his family for their cooperation. This work was supported by the Beijing Municipal Natural Science Foundation (7132068).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Chenlong Yang
    • 1
  • Van Halm-Lutterodt Nicholas
    • 1
  • Jizong Zhao
    • 1
  • Bingquan Wu
    • 2
  • Haohao Zhong
    • 2
  • Yan Li
    • 2
  • Yulun Xu
    • 1
  1. 1.Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
  2. 2.Department of Pathology, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina

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