Cerebral cavernous malformations: from genes to proteins to disease

Clinical article

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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.

Article Information

Address correspondence to: Mark C. Preul, M.D., c/o Neuroscience Publications, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, Arizona 85013. email: mark.preul@chw.edu.

Please include this information when citing this paper: published online September 30, 2011; DOI: 10.3171/2011.8.JNS101241.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Photomicrograph of CCM section highlighting the enlarged capillary channels lined by a thin endothelium, a characteristic finding in this disease. H & E. Original magnification × 40.

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    Axial (upper) and coronal (lower) T1-weighted MR images of a cavernous malformation in the brainstem. The lesion demonstrates the heterogeneous signal characteristics of hemorrhage in various stages of resolution.

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    Schematic representation of the Knudson 2-hit hypothesis for the generation of cancer. The Knudson hypothesis proposes that multiple “hits” are needed for the transformation of a cell into an uncontrolled state of growth. The initial genomic changes can be inherited or acquired during development. It is the accumulation of multiple genomic hits rendering critical growth and remodeling pathways that results in the loss of cell cycle control and unregulated expansion of cell populations in cancer.

  • View in gallery

    Schematic depicting the role of CCM gene products in the organizing of sprouting vascular channels. Modified from Dashti et al.: Neurosurg Focus 21 (1):E2, 2006.

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