A Novel KRIT1/CCM1 Gene Insertion Mutation Associated with Cerebral Cavernous Malformations in a Chinese Family.
Familial cerebral cavernous malformation (FCCM) is a vascular malformation disorder that closely associated with three identified genes: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Here, we present a Chinese family affected by FCCM due to a novel KRIT1/CCM1 insertion mutation. The proband was hospitalized for sudden unconsciousness and underwent surgical treatment. The section of lesions showed classical cavernous-dilated vessels without intervening brain parenchyma, and hemosiderin-laden macrophages were accumulated in the surrounding tissue. In addition, magnetic resonance imaging (MRI) showed severe multiple cerebral cavernous malformation (CCM) lesions in cerebrum, brainstem, and cerebellum in other affected subjects. Especially, for the proband's mother, hundreds of lesions were presented, and a few lesions were found in the expanded lateral ventricle (Evans' index =0.33). Moreover, she showed the similar symptoms of hydrocephalus, including headache, dizziness, and diplopia. It was extremely rare in previous reports. To date, the genetic alterations leading to FCCM in Chinese population remain largely unknown. We investigated genetic defects of this family. Sequence analyses disclosed a novel heterozygous insertion mutation (c.1896_1897insT; p.Pro633SerfsTer22) in KRIT1/CCM1. Moreover, our real-time PCR results revealed that the mRNA level of KRIT1/CCM1 were significantly decreased in FCCM subjects (CCM family =0.42 ± 0.20 vs. healthy control =1.01 ± 0.16, P = 0.004). It indicated that this mutation could cause KRIT1/CCM1 functional mRNA deficiency. It may be closely related with the pathogenesis of FCCM. Our findings provided a new gene mutation profile which will be of great significance in early diagnosis and appropriate clinical surveillance of FCCM patients.
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|China National Clinical Research Center for Neurological Diseases, Beijing, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.|Core Laboratory for Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Hui
H
Wang
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|China National Clinical Research Center for Neurological Diseases, Beijing, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.|Core Laboratory for Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|Department of Neuromuscular and Genetic Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Yunzhu
Y
Pan
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|China National Clinical Research Center for Neurological Diseases, Beijing, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.|Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|Department of Neuromuscular and Genetic Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Zaiqiang
Z
Zhang
Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|Department of Pharmacy, Precision Medicine Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Xingang
X
Li
Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.|Core Laboratory for Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Zhe
Z
Xu
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|China National Clinical Research Center for Neurological Diseases, Beijing, China.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.|Core Laboratory for Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.|Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Yue
Y
Suo
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. lwdoctors@sina.com.|China National Clinical Research Center for Neurological Diseases, Beijing, China. lwdoctors@sina.com.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China. lwdoctors@sina.com.|Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. lwdoctors@sina.com.|Department of Neuromuscular and Genetic Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. lwdoctors@sina.com.
Wei
W
Li
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. yongjunwang1962@gmail.com.|China National Clinical Research Center for Neurological Diseases, Beijing, China. yongjunwang1962@gmail.com.|Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China. yongjunwang1962@gmail.com.|Core Laboratory for Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. yongjunwang1962@gmail.com.|Monogenic Disease Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. yongjunwang1962@gmail.com.
Yongjun
Y
Wang
D000328:Adult; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger
Familial cerebral cavernous malformations; KRIT1/CCM1; Novel mutation