A novel KRIT1/CCM1 truncating mutation in a patient with cerebral and retinal cavernous angiomas

Faculté de Médecine Lariboisière, Laboratoire de Génétique des Maladies Vasculaires, 10 Avenue de Verdun, EPI 99-21, 75010 Paris, Cedex, France.
Archives of Ophthalmology (Impact Factor: 4.4). 03/2002; 120(2):217-8.
Source: PubMed
5 Reads
  • Source
    • "Krit1, which encodes Krev-1/Rap1 interaction trapped 1 protein (KRIT1), is responsible for 40% or more of familial cases of cerebral cavernous malformations (CCM). Since 1999 when Couteulx [9] identified the krit1 responsible for CCM1 located in chromosome 7q21-q22, researchers have revealed that the majority of mutations in krit1, including missense, nonsense and inactive splicing site at various regions, lead to a truncated and presumably inactive KRIT1 [17] [18] [19] [20] . To date, more than 200 different heterozygous mutations have been found scattered throughout all the coding exons of krit1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral Cavernous Malformations (CCM) are vascular malformations that are mostly located in the central nervous system (CNS) and occasionally within the skin and retina, which are classified into three types (CCM1, CCM2 and CCM3) by being located at different loci on chromosomes. At present, CCM1 (7q21), CCM2 (7p13-p15) and CCM3 (3q25.2-q27) are respectively linked to krit1 (Krev interaction trapped gene 1), MGC4607 and PDCD10 (programmed cell death 10). In this work, we identified a novel "GTA" deletion mutation at the acceptor splicing site of intron9/exon10 on krit1. The mutation results in an abnormally spliced protein by creating a premature termination code at the 23rd amino acid downstream from the sequence alteration. Our results are consistent with previous research on krit1 mutations and confirm the conclusion that KRIT1 haploinsufficiency may be the underlying mechanism of CCM1.
    Acta Genetica Sinica 03/2006; 33(2):105-10. DOI:10.1016/S0379-4172(06)60028-0
  • Source
    • "Nearly 100 different KRIT1 germline mutations have been detected in families with CCM. All these mutations lead to premature stop codons through either nonsense, splice-site, frameshift, or false missense mutations, strongly suggesting that Krit1 loss of function is the most likely mechanism in patients with CCM (Laberge-le Couteulx et al. 1999; Sahoo et al. 1999; Eerola et al. 2000; Zhang et al. 2000; Davenport et al. 2001; Lucas et al. 2001; Sahoo et al. 2001; Cave-Riant et al. 2002; Chen et al. 2002; Couteulx et al. 2002; Verlaan et al. 2002; Laurans et al. 2003; Lucas et al. 2003; Marini et al. 2003; Musunuru et al. 2003; Xu et al. 2003). "
    [Show abstract] [Hide abstract]
    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.
    The American Journal of Human Genetics 03/2004; 74(2):326-37. DOI:10.1086/381718 · 10.93 Impact Factor
  • Source
    • "However, many alternative splicing events are very rare and occur only in a specific tissue at a specific time in development (Belkin et al., 1997; Belkin and Retta, 1998) and/or under certain physiological conditions . Multiple and specific Krit1 transcripts were previously detected by Northern blot analysis of mouse and human tissues (Laberge-le Couteulx et al., 1999; Eerola et al., 2001; Kehrer-Sawatzki et al., 2002), suggesting that various and species-specific splice forms of Krit1 might exist. Whereas the structure of most of these transcripts is still elusive, alternative splicing products of the human Krit1 gene, due to differential usage of the four 5V-end untranslated exons (exons À 1 to À 4) or of the coding exons 4 and 5, have been previously reported (Eerola et al., 2001; Sahoo et al., 2001; Kehrer-Sawatzki et al., 2002), although their functional significance is unknown. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral cavernous malformations (CCM) are vascular malformations, mostly located in the central nervous system, which occur in 0.1-0.5% of the population. They are characterized by abnormally enlarged and often leaking capillary cavities without intervening neural parenchyma. Some are clinically silent, whereas others cause seizures, intracerebral haemorrhage or focal neurological deficits. These vascular malformations can arise sporadically or may be inherited as an autosomal dominant condition with incomplete penetrance. At least 45% of families affected with cerebral cavernous malformations harbour a mutation in Krev interaction trapped-1 (Krit1) gene (cerebral cavernous malformation gene-1, CCM1). This gene contains 16 coding exons which encode a 736-amino acid protein containing three ankyrin repeats and a FERM domain. Neither the CCM1 pathogenetic mechanisms nor the function of the Krit1 protein are understood so far, although several hypotheses have been inferred from the predicted consequences of Krit1 mutations as well as from the identification of Krit1 as a binding partner of Rap1A, ICAP1A and microtubules. Here, we report the identification of Krit1B, a novel Krit1 isoform characterized by the alternative splicing of the 15th coding exon. We show that the Krit1B splice isoform is widely expressed in mouse cell lines and tissues, whereas its expression is highly restricted in human. In addition, we developed a real-time PCR strategy to accurately quantify the relative ratio of the two Krit1 alternative transcripts in different tissues, demonstrating a Krit1B/Krit1A ratio up to 20% in mouse thymus, but significantly lower ratios in other tissues. Bioinformatic analysis using exon/gene-prediction, comparative alignment and structure analysis programs supported the existence of Krit1 alternative transcripts lacking the 15th coding exon and showed that the splicing out of this exon occurs outside of potentially important Krit1 structural domains but in a region required for association with Rap1A, suggesting a subtle, yet important effect on the protein function. Our results indicate that maintenance of a proper ratio between Krit1A and Krit1B could be functionally relevant and suggest that the novel Krit1B isoform might expand our understanding of the role of Krit1 in CCM1 pathogenesis.
    Gene 02/2004; 325(1):63-78. DOI:10.1016/j.gene.2003.09.046 · 2.14 Impact Factor
Show more