Molecular genetics of familial cerebral cavernous malformations

Shervin R. Dashti M.D., Ph.D., Alan Hoffer M.D., Yin C. Hu M.D., and Warren R. Selman M.D.
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  • Department of Neurosurgery, University Hospitals of Cleveland, Case School of Medicine, Cleveland, Ohio
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✓Cerebral cavernous malformations (CMs) are angiographically occult neurovascular lesions that consist of enlarged vascular channels without intervening normal parenchyma. Cavernous malformations can occur as sporadic or auto-somal-dominant inherited conditions. Approximately 50% of Hispanic patients with cerebral CMs have the familial form, compared with 10 to 20% of Caucasian patients. There is no difference in the pathological findings or presentation in the sporadic and familial forms. To date, familial CMs have been attributed to mutations at three different loci: CCM1 on 7q21.2, CCM2 on 7p15-p13, or CCM3 on 3q25.2-q27. The authors summarize the current understanding of the molecular events underlying familial CMs.

Abbreviations used in this paper:

CM = cavernous malformation; COX-2 = cyclooxygenase-2; ECM = extracellular matrix; GTPase = guanosine 5′-triphosphatase; ICAP = integrin cytoplasmic domain–associated protein; KRIT = Krev interaction trapped; MAPK = mitogen-activated protein kinase; MEKK3 = MAPK kinase kinase 3; MEK1/2–ERK 1/2 = MAPK kinase 1/2–extracellular signal regulated protein kinase 1/2; OSM = osmosensing scaffold for MEKK3.

✓Cerebral cavernous malformations (CMs) are angiographically occult neurovascular lesions that consist of enlarged vascular channels without intervening normal parenchyma. Cavernous malformations can occur as sporadic or auto-somal-dominant inherited conditions. Approximately 50% of Hispanic patients with cerebral CMs have the familial form, compared with 10 to 20% of Caucasian patients. There is no difference in the pathological findings or presentation in the sporadic and familial forms. To date, familial CMs have been attributed to mutations at three different loci: CCM1 on 7q21.2, CCM2 on 7p15-p13, or CCM3 on 3q25.2-q27. The authors summarize the current understanding of the molecular events underlying familial CMs.

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