Molecular Genetics of Familial Cerebral Cavernous Malformations


Cerebral cavernous malformations (CCMs) are vascular lesions that afflict the central nervous system. The prevalence of CCMs in the general population is 0.1–0.5%, and the disease may present as a sporadic or familial form. The familial form of the disease shows a strong predilection for the Hispanic–American ethnic group. Current research suggests that the familial form of CCMs arises due to mutations that occur in one or more of three genes: CCM1, CCM2 and CCM3, which encode KRIT‐1 protein, malcavernin and programmed cell death 10, respectively. This article examines the known genetic insults to the CCM genes that may cause mutated, nonfunctioning protein products. Each has unique downstream intracellular effects that lead to CCM formation. Recommendations regarding genetic counselling for families with CCMs are presented.

Key Concepts:

  • Genetic Counselling, gross pathology and molecular genetics of CCM, differences in inheritance patterns between familial and sporadic CCM.

  • CCMs are mulberry‐like vascular defects characterized by enlarged, leaky capillaries within the central nervous system.

  • CCMs have a strong predilection for the Hispanic‐American ethnic group and may be present in patients as either a sporadic single lesion or an inherited multi‐lesion form.

  • The most common symptoms for CCM patients with supratentorial vascular lesions are recurrent headaches and seizures whereas infratentorial lesions result in focal neurological defects and ataxia.

  • The familial form of CCM disease is caused by mutations in one or more of the three genes: CCM1, CCM2 and CCM3 whose protein products are relevant to endothelial proliferation regulation, intracellular osmoregulation and endothelial migration, respectively.

  • K‐Rev interaction trapped 1, the protein product of CCM1, is mutated in 56% of the familial CCM patients thus preventing its association with malcavernin and RAP‐1A/ICAP1 α leading to abnormal vascular morphogenesis and dysregulation of sprouting angiogenesis

  • For the familial variant of CCMs, the strong genetic inheritance patterns suggest physicians should recommend patients for genetic screening for CCM1, CCM2 and CCM3 mutations, as well as for patients with solitary lesions and a family history of the disease.

Keywords: cerebral cavernous malformation; KRIT‐1 protein; NPXY motif; malcavernin; PDCD10

Figure 1.

(a) Rho Activation of KRIT‐1 and feedback inhibition of Rho A small GTPase (Rho A). The above diagram depicts KRIT‐1 Rho activation and subsequent KRIT‐1 induced suppression of Rho A. When KRIT‐1 function is down‐regulated by loss of function mutations in CCM1, Rho A activity is unchecked, leading to the various diagramed downstream effects. ECM, extracellular matrix. (b) Proposed mechanism of interactions of KRIT‐1with RAP‐1A (Ia–IVa) and ICAP1α (Ib–IIb). Ia: RAP‐1A may bind RIAM, which recruits the β1 integrin activating protein talin, thus creating a RAP‐1A/RIAM/Talin complex (IIa), or it may bind KRIT‐1 first via its PTB‐containing C‐terminal FERM domain and subsequently be associated with RIAM/talin (IIIa). IVa: The quaternary complex of KRIT‐1/RAP‐1A/RIAM/talin migrates to the plasma membrane, displaces the ICAP1α suppressor, and activates β1 integrin via talin binding. Ib: KRIT‐1 may directly bind and sequester the ICAP1α suppressor from β1 integrin via NPXY/PTB domain interaction (see diagram). This possibility opens the door for talin–integrin activation. IIb: The KRIT‐1/ ICAP1α complex is stabilised and then shuttles between the nucleus and cytoplasm. Loss of KRIT‐1 can lead to destabilisation of ICAP1α and unchecked sprouting angiogesis of cerebral vasculature. (c) The role of KRIT‐1 in intracellular ROS homoeostasis. The intracellular presence of KRIT‐1 maintains intracellular levels of key ROS regulation enzymes. When KRIT‐1 function in lost, buildup of these damaging molecules has been proposed as source of environmental stress leading to CCM formation. Reproduced with permission from Barrow Neurological Institute.

Figure 2.

(a) P38 Activation. MEKK3‐dependent p38 activation requires the Rac‐OSM‐MEKK3‐MKK3, which is stimulated by sorbitol‐induced hyperosmolarity. (b) Molecular interactions of CCM1 and CCM3 with CCM2. The KRIT‐1 and MGC4607 complex results in vascular morphogenesis. The PDCD10 and MGC4607 complex plays an important role in destabilisation of the endothelial cells. Reproduced with permission from Barrow Neurological Institute.

Figure 3.

(a) Molecular interaction of PDCD10/paxillin. PDCD10 binds with paxillin through the interaction of its surface patch protein, HP1, located on the C‐terminus FAT domain with the paxillin motifs, LD1, LD2, LD4. The formation of this complex plays a role in cellular spreading and motility. (b) PDCD10/MST4 interaction causes a cascade of events. The molecular interaction between PDCD10 and MST4 activates the ERM family of proteins and ERK pathway through phosphorylation by MST4. The result is actin filament linking and cellular proliferation, respectively. This protein‐protein interaction also shuttles MST4 from the GM 130 protein on the cis‐Golgi to the STRIPAK complex, assisting in Golgi positioning and cellular migration. Reproduced with permission from Barrow Neurological Institute.



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Further Reading

Abla AA, Lekovic GP, Turner JD et al. (2011) Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single‐center case series of 300 surgically treated patients. Neurosurgery 68(2): 403–414.

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Filippidis AS, Fountas KN, Kalani MY, Zabramski JM and Spetzler RF (2011) Letter by Filippidis et al. regarding article, Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke 42(5): e373 Epub Mar 10 2011.

Vishteh AG, Zabramski JM and Spetzler RF (1999) Patients with spinal cord cavernous malformations are at an increased risk for multiple neuraxis cavernous malformations. Neurosurgery 45(1): 30–32.

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Dru, Alexander, Eales, Justin, Martirosyan, Nikolay L, Mushtaq, Raza, Cavalcanti, Daniel D, Kalani, M Yashar S, Zabramski, Joseph M, Spetzler, Robert F, and Preul, Mark C(Nov 2012) Molecular Genetics of Familial Cerebral Cavernous Malformations. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024307]