Cerebral cavernous malformation (CCM)

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Cerebral cavernous malformation (CCM)

Cerebral cavernous malformation (CCM).  It is speculated that the prevalence of brain “cavernous” or capillary-venous malformation (CCM) (old term: “cerebral cavernous hemangioma”; OMIM#116860) is 1/5000.

The disease has neither gender differences nor early inheritance, that is, one generation of CCM is more serious than one generation (Denier et al., 2006).

The immunohistochemical study of CCM found that fibronectin is expressed in endothelial cells and subendothelial matrix, and it lacks laminin, smooth muscle cells and pericytes (Robinson et al., 1995).

Due to the lack of markers of vasculature maturity, these authors believe that the immature blood vessels in CCM reflect persistent abnormal angiogenesis.

The signs and symptoms of CCM include epilepsy, headache, bleeding, and focal neurological impairment (Giombini and Morello, 1978). These lesions are usually not noticed for several years, and CCM can only be found through autopsy, so the genetic characteristics of the disease are often underestimated.

Several families with autosomal dominant inheritance of CCM have been reported, especially among Hispanic Americans (Mason et al., 1988; Rigamonti et al., 1988; Rigamonti and Spetzler, 1988; Bicknell, 1989).

The first locus found was located in the 7q11.2-q21 chromosomal region (CCMI) (Dubovsky et al., 1995; Gunel et al., 1995; Marchuk et al., 1995). The reason for the higher incidence of CCM among Hispanics is the founder effect, that is, the higher prevalence of ancestral gene mutations (Gunel et al., 1996).

The positional cloning method can clearly lead to CCM1 gene KRITI (KRevInteractionTrapped1) (OMIM#604214) (Laberge-leCouteulx et al., 1999; Sahoo et al., 1999).

Many gene mutations are now known, and most gene mutations can produce premature stop codons, causing them to lose their function (Cave-Riant et al., 2002), especially a very common gene mutation has been found in Hispanics ( Laurans et al., 2003).

The KRITI gene was previously thought to be an intercellular signaling molecule. It was originally thought to be a protein that binds to KREVI/RAP1A in two-hybrid screening, that is, a RAS family GTPase, which acts as a RAS protein antagonist (Serebriski et al., 1977 ) (Figure 9-5), but this interaction has not been confirmed.

In contrast, it has been demonstrated that KRITI can interact with an intercellular integrin binding protein ICAP1a (Zhang et al., 2001; Zawistowski et al., 2002; Beraud-Dufour et al., 2007). KRITI may be involved in the adhesion between cells, but it may also have other important binding functions.

Interestingly, multiple Northern Western blot analysis in all tissues detected KRIT1 hybridization signal, but only affected the central nervous system (Laberge-le Couteulx et al., 1999). It suggests that KRITI plays a specific function in the brain vasculature. It is also interesting that Kritl knockout mice can die of heart problems, while the vasculature of the brain is normal (Kleaveland et al., 2009).

The reason for this phenotypic difference is that rodents are essentially homozygous, but in humans it is very likely to cause premature death. Interestingly, p53 seems to play a role in the tendency of Kritl knockout mice to develop CCM (Plummer et al., 2004).

In addition to the CCMI locus, the other two CCM2 and CCM3 loci are also related to CCM (Craig et al., 1998). In the family studied, these 3 loci contained all hereditary CCM, but the detection of locus heterogeneity did not formally rule out the possibility of the fourth locus (Craig et al., 1998; Liquori et al. , 2006).

CCM2 (OMIM#603284) is located at 7p13, and CCM3 (OMIM#603285) is located at 3q26.1. The mutant CCM2 gene has been named malecawernin (or MGC4067) (0MIM#607929), and CCM3 is named PDCPI0, which is programmed cell death factor 10 (OMIM#609118) (Bergametti et al., 2005).

Liquori and colleagues (2003) and Denier and colleagues (2004) found that several gene mutations in CCM2 can lead to the appearance of premature stop codons or partial deletion of genes, which is very likely to cause the loss of malcavernin function.

Similarly, mutations in the CCM3 gene may cause non-functional proteins and haploinsufficiency (Berga-metti et al., 2005). Studies have shown that 40% of the tested families are related to CCM1, 20% are related to CCM2, and 40% are related to CCM3.

The penetrance rate is significantly different, the penetrance rate of CCM1 is 88%, CCM2 is 100%, and CCM3 is 63% (Craig et al., 1998; Revencu and Vikkula, 2006).

It has been demonstrated that CCM1 and CCM2, CCM2 and CCM3 can interact (Zawistowski et al., 2005; Voss et al., 2007) (Figure 9-5).

The dysfunction of the CCM signaling complex caused by the mutation of CCM1~3 gene can lead to the continuous activity of RhoA and its effector molecule ROCK, which changes the integrity of blood vessels and the organization of endothelial cells (Borikova et al., 2010; Stockton et al., 2010). Important downstream effector molecules of CCM3 are sterile20 serine/threonine kinase 24 (STK24) and STK25.

In zebrafish embryos, these gene deficiencies can lead to the typical symptoms of CCM deficiency (Zheng et al., 2010). CCM2 interacts with p38, thereby participating in the MAP kinase signaling pathway (Zawistowski et al., 2005).

Therefore, there may be a separate molecular pathway that causes CCM (Chan et al., 2011).

(source:internet, reference only)

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