当前位置： SCI文献检索 > AMERICAN JOURNAL OF HUMAN GENETICS期刊下所有文献 > Mutations within the MGC4607 gene cause cerebral cavernous malformations.

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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Denier C,Goutagny S,Labauge P,Krivosic V,Arnoult M,Cousin A,Benabid AL,Comoy J,Frerebeau P,Gilbert B,Houtteville JP,Jan M,Lapierre F,Loiseau H,Menei P,Mercier P,Moreau JJ,Nivelon-Chevallier A,Parker F,Redondo AM,S

doi

10.1086/381718

subject

Has Abstract

pub_date

2004-02-01 00:00:00

pages

326-37

issue

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(07)61843-6

journal_volume

pub_type

杂志文章

在线工具

Mutations within the MGC4607 gene cause cerebral cavernous malformations.