By Cornelia Lee, PsyD, Judith Gault, PhD, Emily Crocker, MS, Tracey Leedom, MS, and Amy Akers, PhD
A gene is the basic unit of heredity. Genes are made from DNA, the building block of life, and carry the information for creating the proteins which are the functional units that perform a particular characteristic or function. When a gene mutates, it changes from its natural state and can cause an illness. Genetic mutations can be inherited from your parent (and therefore, occur in every cell in your body), or acquired by single cells in your body throughout a lifetime.
Cerebral cavernous malformations (cavernous angiomas) can occur either sporadically, or they may run in families and be inherited due to a genetic mutation. With familial cavernous malformations, a mutation of a specific gene has occurred in every cell of your body. While it is still not known why sporadic lesions form, it is believed that acquired genetic mutations occurr in just one cell in your body and cause the formation of a sporadic cavernous angioma.
You may have one cavernous malformation and have no other family members with the illness. It is believed that a majority of those diagnosed with the illness fall into this category. The cause of sporadic cavernous malformations is not known. However, it is thought that a solitary cavernous malformation can be formed when a single cell has two specific mutations, or changes in both copies of a particular gene. As that cell replicates and divides, it goes on to form the cavernous malformation.
A solitary cavernous malformation may be present at birth or may form later. If you have a sporadic cavernous malformation, it is likely that your children would have no greater chance of having the illness than anyone in the general population.
In certain instances, individuals with the sporadic form of the illness have more than one cavernous malformation. This can be true if the individual has a developmental venous malformation (also known as a venous anomaly or venous angioma) or if they have undergone radiation treatments in the brain or spinal cord. As MRI technology has improved, there are also more cases in which small blood vessel leakage associated with aging is interpreted as the development of a new cavernous malformation when it is not. If you have more than one cavernous malformation and don't appear to have a family history of the illness, a knowledgeable physician possibly combined with genetic testing is an appropriate approach to determining if you have the hereditary form.
Familial cavernous malformations are caused by a single gene mutation in any one of at least three different genes. A mutation on any one of three genes (CCM1, CCM2, or CCM3) can cause the illness. If you have familial cavernous malformation, this illness may run in your family or you may be the first in your family to have the illness. You may have just one cavernous malformation, but are likely to have multiple cavernous malformations.
Familial cavernous malformation is a hereditary illness that is an autosomal dominant condition. This means that only one parent must have the illness for it to be passed on to offspring. Statistically, if you have the familial form of the illness and you have a child with someone who does not, your child will have a 50% chance of having the illness.
If you are the first in your family to have multiple cavernous malformations, you are likely to be the first in your family to have a familial mutation. This puts your risk of passing on the illness to your children at 50%.
Familial cavernous malformations are caused by a genetic mutation found in every cell in your body, rather than a mutation in a single cell (sporadic cases). We each have two copies of any gene. When one copy mutated, causing it to no longer function correctly, the other copy is a backup that will perform the same function. However, the backup must work perfectly to avoid any problems caused by the original mutation. Because of naturally occurring, random genetic mutations - this is almost never the case for every cell in the body.
In the case of familial cavernous malformation, a mutation on the first copy of the gene causes it to stop functioning. Intermittent but naturally occurring problems (acquired mutations) with the backup gene copy in some cells cause the formation of cavernous malformations. Wherever the backup gene fails, a cavernous malformation develops. As a result, if you have familial cavernous malformations you are likely to have more than one malformation. It is thought that almost everyone with the familial form will eventually have multiple cavernous malformations.
To date, three genes have been identified to cause the familial form of cavernous malformation. The first gene was identified in 1999 and was named CCM1 (for cerebral cavernous malformation 1). Subsequently, CCM2 was identified in 2003, and CCM3 was found in 2005. Each of these genes were named ‘CCM' because, when they were identified they were each novel genes with entirely unknown functions. Since their discoveries, researchers have been working to determine the function of these genes, and why mutation of any one causes onset of cavernous malformation.
About 40% of familial cavernous malformation is caused my mutations in the CCM1 gene. Additionally, this is the gene responsible for most of the cases of familial multiple cavernous malformation in Hispanic families. In fact, most Hispanics with a specific CCM1 mutation (the Common Hispanic Mutation) are thought to share a common ancestor that can be traced back at least 17 generations.
CCM1 is responsible for creating the CCM1 protein, also called KRIT1, or Krev interaction-trapped 1 protein. This protein is considered to be important for basic life development, mice that are mutant for both copies of CCM1 die very early in development, prior to birth. The exact function of KRIT1 protein is not known, but it is believed to play a role in determining and maintaining the structure of endothelial cells in blood vessels in the brain.
The second gene is called CCM2 and controls the production of a protein named malcavernin. The malcavernin protein is also an essential protein for life - it is needed for cardiovascular development and to maintain the structure of blood vessels. Nearly 40% of familial cavernous malformation can be linked to a CCM2 mutation. Approximately half of affected individuals in the United States who have a CCM2 mutation, have a specific mutation that deletes a majority of the CCM2 gene.
The third gene, CCM3, is responsible for creating a protein called Programmed Cell Death 10 or PDCD10. The name of the protein refers to this gene's function in regulating cell survival. How this function pertains to cavernous malformation illness remains unknown; however, recent evidence suggests that CCM3 also functions to control the structure of blood vessels. Mutations in the CCM3 gene account for nearly 10% of familial cases of the illness.
About 10% of families with a history of cavernous angioma have no mutations in any of the known CCM genes. Thus, there remains a possibility that a 4th
CCM gene may be discovered in the future.
For more information on these three genes, please visit the Genetics Home Reference. Genetics Home Reference is a service of the National Library of Medicine. These are the links:
CCM1 (KRIT1): http://ghr.nlm.nih.gov/gene=krit1
CCM2 (malcavernin): http://ghr.nlm.nih.gov/gene=ccm2
CCM3 (PDCD10): http://ghr.nlm.nih.gov/gene=pdcd10
Clinical genetic testing, the only kind of testing that can be used for diagnosis, is available for all three currently known genes. See our Genetic Testing page to find specific laboratories that have been approved to perform these tests. Because not all of the genes have been identified, genetic testing can not rule out a familial mutation. However, if a mutation is identified, it becomes very easy and economical to test other family members.
Whether to have genetic testing is a very personal decision. Please make sure that you have a knowledgeable genetic counselor or physician to help guide you.
Many researchers working on cavernous malformations are focused on genetic issues. It seems to hold the most promise for future understanding and eventual cure. The current focus is on identifying the precise functions of the proteins created by the genes. Please see our newsletter and our blog for ongoing information about genetic discoveries in this area.
To find general information on genetics, visit GeneTests or the Genetics Home Reference.
Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): Evidence for a two-hit mechanism for CCM pathogenesis. Hum Mol Genet. 2009 Mar1;18(5):919-30.
Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E; Societe Francaise de Neurochirurgie.
Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet. 2005 Jan;76(1):42-51.
Borikova AL, Dibble CF, Sciaky N, Welch CM, Abell AN, Bencharit S, Johnson GL. Rho Kinase Inhibition Rescues the Endothelial Cell Cerebral Cavernous Malformation Phenotype. J Biol Chem. 2010 Apr 16;285(16):11760-4
Craig HD, Gunel M, Cepeda O, Johnson EW, Ptacek L, Steinberg GK, Ogilvy CS, Berg MJ, Crawford SC, Scott RM, Steichen-Gersdorf E, Sabroe R, Kennedy CTC, Mettler G, Beis M. J, Fryer A, Awad IA, LiftonRP, Multilocus linkage identifies two new loci for a Mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum. Molec. Genet. 7: 1851-1858, 1998.
Gault J, Shenkar R, Reckseik P, Awad IA. Biallelic somatic and germline CCM1 truncating mutations in cerebral cavernous malformation lesion. Stroke. 2005 Apr;36(4):872-4.
He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, Min W. Stabilization of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 Is Critical for Vascular Development. Cell Biol. 2010 Apr; 3(116).
Hsu F, Rigamonti D, and Huhn S. Epidemiology of cavernous malformations. In: Awad I and Barrow D., eds. Cavernous Malformations. Park Ridge, Ill.: American Association of Neurological Surgeons; 1993:13-23.
Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA.
Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet. 73(6):1459-64, Dec 2003.
Liquori CL, Berg MJ, Squitieri F, Leedom TP, Ptacek L, Johnson EW, Marchuk DA. Deletions in CCM2 are a common cause of cerebral cavernous malformations. Am j Hum Genet. 2007 Jan;80(1):69-75.
Pagenstecher A, Stahl S, Sure U, Felbor U. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2, or CCM3 in affected endothelial cells. Hum Mol Genet. 2009 Mar;18(5):911-8.
Stockton RA, Shenkar R, Awad IA, Ginsberg MH. Cereberal cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp med. 2010 Apr 12;207(4):881-96.
Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, Mayo AH, Drakos SG, Marchuk DA, Davis GE, Li DY. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. 2009 Feb; 15(2):177-84.Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL, Marchuk DA.
CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet. 2005 Sep 1;14(17):2521-31.
This page was last updated 1/06/11