Mutations within the MGC4607 Gene Cause Cerebral Cavernous Malformations

Abstract

Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.

Familial brain arteriovenous malformation maps to 5p13–q14, 15q11–q13 or 18p11: Linkage analysis with clipped fingernail DNA on high-density SNP array

“…The three regions do not overlap with a previously reported candidate locus of familial brain AVM, i.e. 6p25 [17], and do not contain genes responsible for syndromic AVM (heritable disorders involving AVM) or cerebral cavernous malformations, such as ENG [6], ALK1 [7], RASA1 [8][9][10][11][12], and PTEN [13], KRIT1 [14], MGC407 [15], PDCD10 [16].…”

“…No causative mutation or genomic aberration was detected in the proband. Although other genes, such as KRIT1, MGC407 and PDCD10, have been shown to cause slow-flow lesions i.e., cerebral cavernous malformation [14][15][16], they were not investigated in the present study, because the clinical manifestations in our family did not meet the criteria for these diseases.…”

“…Although several causative genes have been elucidated in some heritable syndromic AVM [6][7][8][9][10][11][12][13][14][15][16], molecular genetic studies of familial or sporadic AVM remain scant.…”

“…Mutations in PTEN have been implicated in PTEN hamartoma tumor syndromes including Bannayan-Riley-Ruvalcaba syndrome, in which AVM occasionally presents [13]. Three genes, KIRIT1 (CCM1) [14] at 7q21.2, MGC4607 (CCM2) [15] at 7p13 and PDCD10 (CCM3) [16] at 3q26.1, are responsible for cerebral cavernous malformation (hamartomatous vascular malformations). On the other hand, regarding familial AVM, only two linkage analyses using 6 small families have been published by a research group [17,18], showing seven possible disease-responsible regions, i.e., 6q25 with the highest LOD score, 3p27, 4q34, 7p21, 13q32-q33, 16p13-q12 and 20q11-q13, but failed to identify the causative mutation.…”

CCM1 and the second life of proteins in adhesion complexes

“…33,34 Later on, two other genes were found to be associated with CCM, CCM2/ OSM (osmosensing protein 1)/Malcavernin 35,36 and CCM3/ PDCD10 (programmed cell death 10). 37,38 Over 150 different germline mutations are identified in either one of these genes, predominantly resulting in loss of function.…”