title: 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.
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.
authors.affiliation: Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China.
authors.forename: Chenlong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China.
authors.forename: Van Halm-Lutterodt
authors.initials: VH
authors.lastname: Nicholas
authors.affiliation: Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China.
authors.forename: Jizong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, No. 38 Xueyuan Road, Haidian District, Beijing, 100191, China.
authors.forename: Bingquan
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, No. 38 Xueyuan Road, Haidian District, Beijing, 100191, China.
authors.forename: Haohao
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, No. 38 Xueyuan Road, Haidian District, Beijing, 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China. xuhuxi@sina.com.
authors.forename: Yulun
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000328:Adult; D018389:Codon, Nonsense; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D000075927:KRIT1 Protein; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins
keywords: CCM1/KRIT1; Cerebral cavernous malformation; Familial cerebral cavernous malformation; Nonsense mutation; Novel mutation