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.

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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.

  • View in gallery

    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.

  • View in gallery

    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.

References

1

Abe MKjellberg RNAdams RD: Clinical presentations of vascular malformations of the brain stem: comparison of angiographically positive and negative types. J Neurol Neurosurg Psychiatry 52:1671751989

2

Béraud-Dufour SGautier RAlbiges-Rizo CChardin PFaurobert E: Krit 1 interactions with microtubules and membranes are regulated by Rap1 and integrin cytoplasmic domain associated protein-1. FEBS J 274:551855322007

3

Bergametti FDenier CLabauge PArnoult MBoetto SClanet M: Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76:42512005

4

Bicknell JM: Familial cavernous angioma of the brain stem dominantly inherited in Hispanics. Neurosurgery 24:1021051989

5

Bicknell JMCarlow TJKornfeld MStovring JTurner P: Familial cavernous angiomas. Arch Neurol 35:7467491978

6

Bos JL: All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral. EMBO J 17:677667821998

7

Bouffard GGIdol JRBraden VVIyer LMCunningham AFWeintraub LA: A physical map of human chromosome 7: an integrated YAC contig map with average STS spacing of 79 kb. Genome Res 7:6736921997

8

Cavé-Riant FDenier CLabauge PCécillon MMaciazek JJoutel A: Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations. Eur J Hum Genet 10:7337402002

9

Chang DDWong CSmith HLiu J: ICAP-1, a novel beta1 integrin cytoplasmic domain-associated protein, binds to a conserved and functionally important NPXY sequence motif of beta1 integrin. J Cell Biol 138:114911571997

10

Chen LTanriover GYano HFriedlander RLouvi AGunel M: Apoptotic functions of PDCD10/CCM3, the gene mutated in cerebral cavernous malformation 3. Stroke 40:147414812009

11

Clark JV: Familial occurrence of cavernous angiomata of the brain. J Neurol Neurosurg Psychiatry 33:8718761970

12

Clatterbuck REEberhart CGCrain BJRigamonti D: Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations. J Neurol Neurosurg Psychiatry 71:1881922001

13

Craig HDGünel MCepeda OJohnson EWPtacek LSteinberg GK: Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2–27. Hum Mol Genet 7:185118581998

14

Czubayko MKnauth PSchlüter TFlorian VBohnensack R: Sorting nexin 17, a non-self-assembling and a PtdIns(3)P high class affinity protein, interacts with the cerebral cavernous malformation related protein KRIT1. Biochem Biophys Res Commun 345:126412722006

15

Davenport WJSiegel AMDichgans JDrigo PMammi IPereda P: CCM1 gene mutations in families segregating cerebral cavernous malformations. Neurology 56:5405432001

16

Del Curling O JrKelly DL JrElster ADCraven TE: An analysis of the natural history of cavernous angiomas. J Neurosurg 75:7027081991

17

Denier CGoutagny SLabauge PKrivosic VArnoult MCousin A: Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 74:3263372004

18

Denier CLabauge PBergametti FMarchelli FRiant FArnoult M: Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann Neurol 60:5505562006

19

Di Rocco CIannelli ATamburrini G: Cavernous angiomas of the brain stem in children. Pediatr Neurosurg 27:92991997

20

Dobyns WBMichels VVGroover RVMokri BTrautmann JCForbes GS: Familial cavernous malformations of the central nervous system and retina. Ann Neurol 21:5785831987

21

Dubovsky JZabramski JMKurth JSpetzler RFRich SSOrr HT: A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 4:4534581995

22

Eerola IMcIntyre BVikkula M: Identification of eight novel 5′-exons in cerebral capillary malformation gene-1 (CCM1) encoding KRIT1. Biochim Biophys Acta 1517:4644672001

23

Felbor UGaetzner SVerlaan DJVijzelaar RRouleau GASiegel AM: Large germline deletions and duplication in isolated cerebral cavernous malformation patients. Neurogenetics 8:1491532007

24

Flocks JSWeis TPKleinman DCKirsten WH: Dose-response studies to polyoma virus in rats. J Natl Cancer Inst 35:2592841965

25

Fritschi JAReulen HJSpetzler RFZabramski JM: Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir (Wien) 130:35461994

26

Gaetzner SStahl SSürücü OSchaafhausen AHalliger-Keller BBertalanffy H: CCM1 gene deletion identified by MLPA in cerebral cavernous malformation. Neurosurg Rev 30:1551602007

27

Gault JShenkar RRecksiek PAwad IA: Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 36:8728742005

28

Gianfrancesco FEsposito TPenco SMaglione VLiquori CLPatrosso MC: ZPLD1 gene is disrupted in a patient with balanced translocation that exhibits cerebral cavernous malformations. Neuroscience 155:3453492008

29

Gil-Nagel ADubovsky JWilcox KJStewart JMAnderson VELeppik IE: Familial cerebral cavernous angioma: a gene localized to a 15-cM interval on chromosome 7q. Ann Neurol 39:8078101996. (Erratum in Ann Neurol 39:480 1996)

30

Gil-Nagel AWilcox KJStewart JMAnderson VELeppik IERich SS: Familial cerebral cavernous angioma: clinical analysis of a family and phenotypic classification. Epilepsy Res 21:27361995

31

Giombini SMorello G: Cavernous angiomas of the brain. Account of fourteen personal cases and review of the literature. Acta Neurochir (Wien) 40:61821978

32

Glading AHan JStockton RAGinsberg MH: KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol 179:2472542007

33

Glading AJGinsberg MH: Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling. Dis Model Mech 3:73832010

34

Green EDBraden VVFulton RSLim RUeltzen MSPeluso DC: A human chromosome 7 yeast artificial chromosome (YAC) resource: construction, characterization, and screening. Genomics 25:1701831995

35

Green EDGreen P: Sequence-tagged site (STS) content mapping of human chromosomes: theoretical considerations and early experiences. PCR Methods Appl 1:77901991

36

Greenberger SBoscolo EAdini IMulliken JBBischoff J: Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 362:100510132010

37

Günel MAwad IAAnson JLifton RP: Mapping a gene causing cerebral cavernous malformation to 7q11.2–q21. Proc Natl Acad Sci U S A 92:662066241995

38

Gunel MAwad IAFinberg KAnson JASteinberg GKBatjer HH: A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. N Engl J Med 334:9469511996

39

Gunel MLaurans MSShin DDiLuna MLVoorhees JChoate K: KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein. Proc Natl Acad Sci U S A 99:10677106822002

40

Guzeloglu-Kayisli OAmankulor NMVoorhees JLuleci GLifton RPGunel M: KRIT1/cerebral cavernous malformation 1 protein localizes to vascular endothelium, astrocytes, and pyramidal cells of the adult human cerebral cortex. Neurosurgery 54:9439492004

41

Guzeloglu-Kayisli OKayisli UAAmankulor NMVoorhees JRGokce ODiLuna ML: Krev1 interaction trapped-1/cerebral cavernous malformation-1 protein expression during early angiogenesis. J Neurosurg 100:5 Suppl Pediatrics4814872004

42

Hallmann RHorn NSelg MWendler OPausch FSorokin LM: Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85:97910002005

43

Hayman LAEvans RAFerrell REFahr LMOstrow PRiccardi VM: Familial cavernous angiomas: natural history and genetic study over a 5-year period. Am J Med Genet 11:1471601982

44

Henkemeyer MRossi DJHolmyard DPPuri MCMbamalu GHarpal K: Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 377:6957011995

45

Hogan BMBussmann JWolburg HSchulte-Merker S: Ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish. Hum Mol Genet 17:242424322008

46

Johnson EWIyer LMRich SSOrr HTGil-Nagel AKurth JH: Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig. Genome Res 5:3683801995

47

Kehrer-Sawatzki HWilda MBraun VMRichter HPHameister H: Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1). Acta Neuropathol 104:2312402002

48

Kere JRuutu TDavies KARoninson IBWatkins PCWinqvist R: Chromosome 7 long arm deletion in myeloid disorders: a narrow breakpoint region in 7q22 defined by molecular mapping. Blood 73:2302341989

49

Kidd HACumings JN: Cerebral angiomata in an Icelandic family. Lancet 1:7471947

50

Knudson AG: Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:1571622001

51

Kondziolka DLunsford LDKestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 83:8208241995

52

Krebs LTXue YNorton CRShutter JRMaguire MSundberg JP: Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14:134313522000

53

Kufs H: Über heredofamiliare Angiomatose des Gehirns und der Retina, ihre Beziehungen zueinander und zur Angiomatose der Haut. Z Gesamte Neurol Psychiatr 113:6516861928

54

Kurth JHZabramski JMDubovsky J: Genetic linkage of the familial cavernous malformation (CM) gene to chromosome 7q. Am J Hum Genet 55:Suppl 3A151994. (http://www.osti.gov/energycitations/product.biblio.jsp?osti_id=133322) [Accessed August 23 2011]

55

Labauge PLaberge SBrunereau LLevy CTournier-Lasserve E: Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Société Française de Neurochirurgie. Lancet 352:189218971998

56

Laberge SLabauge PMaréchal EMaciazek JTournier-Lasserve E: Genetic heterogeneity and absence of founder effect in a series of 36 French cerebral cavernous angiomas families. Eur J Hum Genet 7:4995041999

57

Laberge-le Couteulx SJung HHLabauge PHoutteville JPLescoat CCecillon M: Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23:1891931999

58

Liquori CLBerg MJSiegel AMHuang EZawistowski JSStoffer T: Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73:145914642003

59

Liquori CLBerg MJSquitieri FLeedom TPPtacek LJohnson EW: Deletions in CCM2 are a common cause of cerebral cavernous malformations. Am J Hum Genet 80:69752007

60

Liquori CLBerg MJSquitieri FOttenbacher MSorlie MLeedom TP: Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat 27:1182006

61

Liquori CLPenco SGault JLeedom TPTassi LEsposito T: Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9:25312008

62

Lloyd-Jones DAdams RJBrown TMCarnethon MDai SDe Simone G: Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121:e46e2152010. (Erratum in Circulation 121: e260 2010)

63

Lonjon MRoche JLGeorge BMourier KLPaquis PLot G: [Intracranial cavernoma. 30 cases.]. Presse Med 22:9909941993. (Fr)

64

Lucas MCosta AFGarcía-Moreno JMSolano FGamero MAIzquierdo G: Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene. BMC Neurol 3:52003

65

Lucas MCosta AFMontori MSolano FZayas MDIzquierdo G: Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations. Ann Neurol 49:5295322001

66

Ma XZhao HShan JLong FChen YChen Y: PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway. Mol Biol Cell 18:196519782007

67

Mably JDChuang LPSerluca FCMohideen MAChen JNFishman MC: Santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish. Development 133:313931462006

68

Marchuk DAGallione CJMorrison LAClericuzio CLHart BLKosofsky BE: A locus for cerebral cavernous malformations maps to chromosome 7q in two families. Genomics 28:3113141995

69

Mason IAase JMOrrison WWWicks JDSeigel RSBicknell JM: Familial cavernous angiomas of the brain in an Hispanic family. Neurology 38:3243261988

70

Matos PSkaug JMarques BBeck SVeríssimo FGespach C: Small GTPase Rac1: structure, localization, and expression of the human gene. Biochem Biophys Res Commun 277:7417512000

71

McCormick WF: The pathology of vascular (“arteriovenous”) malformations. J Neurosurg 24:8078161966

72

Michael JCLevin PM: Multiple telangiectases of the brain: a discussion of hereditary factors in their development. Arch Neurol Psychiatry 36:5145291936

73

Moriarity JLWetzel MClatterbuck REJavedan SSheppard JMHoenig-Rigamonti K: The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 44:116611731999

74

Moussa RHarb AMenassa LRisk TNohra GSamaha E: [Etiologic spectrum of intracerebral hemorrhage in young patients.]. Neurochirurgie 52:2–3 Pt 11051092006. (Fr)

75

Nibert MHeim S: Uterine leiomyoma cytogenetics. Genes Chromosomes Cancer 2:3131990

76

Otten PPizzolato GPRilliet BBerney J: [131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies.]. Neurochirurgie 35:82831989. (Fr)

77

Pagenstecher AStahl SSure UFelbor U: A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum Mol Genet 18:9119182009

78

Pizon VChardin PLerosey IOlofsson BTavitian A: Human cDNAs rap1 and rap2 homologous to the Drosophila gene Dras3 encode proteins closely related to ras in the ‘effector’ region. Oncogene 3:2012041988

79

Plummer NWGallione CJSrinivasan SZawistowski JSLouis DNMarchuk DA: Loss of p53 sensitizes mice with a mutation in Ccm1 (KRIT1) to development of cerebral vascular malformations. Am J Pathol 165:150915182004

80

Plummer NWSquire TLSrinivasan SHuang EZawistowski JSMatsunami H: Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations. Mamm Genome 17:1191282006

81

Porter PJWillinsky RAHarper WWallace MC: Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 87:1901971997

82

Reedquist KARoss EKoop EAWolthuis RMZwartkruis FJvan Kooyk Y: The small GTPase, Rap1, mediates CD31-induced integrin adhesion. J Cell Biol 148:115111582000

83

Rigamonti DHadley MNDrayer BPJohnson PCHoenig-Rigamonti KKnight JT: Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 319:3433471988

84

Robinson JRAwad IALittle JR: Natural history of the cavernous angioma. J Neurosurg 75:7097141991

85

Ruggieri RBender AMatsui YPowers STakai YPringle JR: RSR1, a ras-like gene homologous to Krev-1 (smg21A/rap1A): role in the development of cell polarity and interactions with the Ras pathway in Saccharomyces cerevisiae. Mol Cell Biol 12:7587661992

86

Russell DSRubinstein LJ: Pathology of Tumours of the Nervous System LondonE. Arnold1989. 730736

87

Sahoo TGoenaga-Diaz ESerebriiskii IGThomas JWKotova ECuellar JG: Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene. Genomics 71:1231262001

88

Sahoo TJohnson EWThomas JWKuehl PMJones TLDokken CG: Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 8:232523331999

89

Schouten JPMcElgunn CJWaaijer RZwijnenburg DDiepvens FPals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e572002

90

Sedgwick SGSmerdon SJ: The ankyrin repeat: a diversity of interactions on a common structural framework. Trends Biochem Sci 24:3113161999

91

Seker APricola KLGuclu BOzturk AKLouvi AGunel M: CCM2 expression parallels that of CCM1. Stroke 37:5185232006

92

Serebriiskii IEstojak JSonoda GTesta JRGolemis EA: Association of Krev-1/rap1a with Krit1, a novel ankyrin repeatcontaining protein encoded by a gene mapping to 7q21–22. Oncogene 15:104310491997

93

Simard JMGarcia-Bengochea FBallinger WE JrMickle JPQuisling RG: Cavernous angioma: a review of 126 collected and 12 new clinical cases. Neurosurgery 18:1621721986

94

Stahl SGaetzner SVoss KBrackertz BSchleider ESürücü O: Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex. Hum Mutat 29:7097172008

95

Stockton RAShenkar RAwad IAGinsberg MH: Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med 207:8818962010

96

Tanriover GBoylan AJDiluna MLPricola KLLouvi AGunel M: PDCD10, the gene mutated in cerebral cavernous malformation 3, is expressed in the neurovascular unit. Neurosurgery 62:9309382008

97

Tomlinson FHHouser OWScheithauer BWSundt TM JrOkazaki HParisi JE: Angiographically occult vascular malformations: a correlative study of features on magnetic resonance imaging and histological examination. Neurosurgery 34:7928001994

98

Uhlik MTAbell ANJohnson NLSun WCuevas BDLobel-Rice KE: Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol 5:110411102003

99

Verlaan DJSiegel AMRouleau GA: Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation. Am J Hum Genet 70:156415672002

100

Voigt KYaşargil MG: Cerebral cavernous haemangiomas or cavernomas. Incidence, pathology, localization, diagnosis, clinical features and treatment Review of the literature and report of an unusual case. Neurochirurgia (Stuttg) 19:59681976

101

Voss KStahl SSchleider EUllrich SNickel JMueller TD: CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics 8:2492562007

102

Wang HUChen ZFAnderson DJ: Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93:7417531998

103

Wang YLiu HZhang YMa D: cDNA cloning and expression of an apoptosis-related gene, humanTFAR15 gene. Sci China C Life Sci 42:3233291999

104

Wernig FMayr MXu Q: Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways. Hypertension 41:9039112003

105

Whitehead KJChan ACNavankasattusas SKoh WLondon NRLing J: The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med 15:1771842009. (Erratum in Nat Med 15:462 2009)

106

Whitehead KJPlummer NWAdams JAMarchuk DALi DY: Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development 131:143714482004

107

Wienecke RMaize JC JrReed JAde Gunzburg JYeung RSDeClue JE: Expression of the TSC2 product tuberin and its target Rap1 in normal human tissues. Am J Pathol 150:43501997

108

Wojnowski LZimmer AMBeck TWHahn HBernal RRapp UR: Endothelial apoptosis in Braf-deficient mice. Nat Genet 16:2932971997

109

Wong JHAwad IAKim JH: Ultrastructural pathological features of cerebrovascular malformations: a preliminary report. Neurosurgery 46:145414592000

110

Zabramski JMWascher TMSpetzler RFJohnson BGolfinos JDrayer BP: The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:4224321994

111

Zawistowski JSSerebriiskii IGLee MFGolemis EAMarchuk DA: KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Hum Mol Genet 11:3893962002

112

Zawistowski JSStalheim LUhlik MTAbell ANAncrile BBJohnson GL: CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet 14:252125312005

113

Zhang JClatterbuck RERigamonti DChang DDDietz HC: Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum Mol Genet 10:295329602001

114

Zhang JClatterbuck RERigamonti DDietz HC: Cloning of the murine Krit1 cDNA reveals novel mammalian 5′ coding exons. Genomics 70:3923952000

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