Cerebral cavernous malformations: from genes to proteins to disease

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  • Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona
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Over the past half century molecular biology has led to great advances in our understanding of angio- and vasculogenesis and in the treatment of malformations resulting from these processes gone awry. Given their sporadic and familial distribution, their developmental and pathological link to capillary telangiectasias, and their observed chromosomal abnormalities, cerebral cavernous malformations (CCMs) are regarded as akin to cancerous growths. Although the exact pathological mechanisms involved in the formation of CCMs are still not well understood, the identification of 3 genetic loci has begun to shed light on key developmental pathways involved in CCM pathogenesis. Cavernous malformations can occur sporadically or in an autosomal dominant fashion. Familial forms of CCMs have been attributed to mutations at 3 different loci implicated in regulating important processes such as proliferation and differentiation of angiogenic precursors and members of the apoptotic machinery. These processes are important for the generation, maintenance, and pruning of every vessel in the body. In this review the authors highlight the latest discoveries pertaining to the molecular genetics of CCMs, highlighting potential new therapeutic targets for the treatment of these lesions.

Abbreviations used in this paper:

BAC = bacterial artificial chromosome; CCM = cerebral cavernous malformation; ERK = extracellular signal-regulated kinase; ICAP-1 = integrin cytoplasmic domain–associated protein 1; lod score = logarithm of odds score; MAPK = mitogen-activated protein kinase; MEKK3 = MAPK-ERK kinase kinase 3; MLPA = multiplex ligation-dependent probe amplification; PAC = plasmid artificial chromosome; PTB = phosphotyrosine binding; YAC = yeast artificial chromosome.

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