title: 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.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing, China.
authors.forename: Chenlong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing, 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, Beijing, 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, Beijing, 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, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. xuhuxi@sina.com.|China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing, China. xuhuxi@sina.com.
authors.forename: Yulun
authors.initials: Y
authors.lastname: Xu
mesh_terms: D020785:Central Nervous System Vascular Malformations / Q000175:diagnosis / Q000235:genetics*; D018389:Codon, Nonsense; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007438:Introns; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012326:RNA Splicing
chemical_list: D018389:Codon, Nonsense; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins
keywords: CCM1; DNA sequencing; Deletion mutation; Familial cerebral cavernous malformation; Novel mutation; Splice-site mutation