Identifying And Cloning The Gene Responsible For Cerebral Cavernous Malformations In A Chinese Family

Cerebral Cavernous Malformation (CCM) as a common disease, clinically classified into familial heredity and sporadic cases. Familial cerebral cavernous malformation is an autosomal dominant disorder producing vascular anomalies throughout the central nervous system (CNS) associated with seizures and hemorrhagic stroke. It is difficult to cure because the genes and pathogenesis are poorly understood. There is great potentiality in medical treatment for the frequent incidence of the disease. Therefore, the research of CCM has been one of the focuses in medicine and molecular genetics. Nowadays, linkage analysis has shown evidence for at least three genetic loci underlying this disorder: CCM1 on chromosome 7q21-q22, CCM2 on chromosome 7p13-p15, and CCM3 on chromosome 3q25.2-q27. Three genes have been cloned: krit1 for the CCM1, MGC4607 for the CCM2, and PDC10 for the CCM3.In our work, we using genetic markers located the responsible gene to 7q21.2-q22 in one Chinese family with cerebral cavernous malformation by linkage analysis. We detected mutation of kritl by direct sequencing in both directions. A "gTA" deletion was found in all affected individuals but no mutation was identified in unaffected individuals in the family, which indicates the deletion mutation cosegregating together with CCM1. The "gTA" deletion locates on acceptor splicing site in intron9/exon10 of krit1, in which "g" composes of the "GT...AG" rule of intron9 acceptor splicing site, while "TA" (nt!255-ntl256) is the initial terminal of exonlO. Our result makes sure that krit1 is the responsible gene of CCM1, and holds out that CCM1 exists in Asian community. In addition, we discussed the action, and the manner of the action, of KRIT1 in vivo, and researched the potential pathogenesis in CCM1.