New insights into mechanisms of small vessel disease stroke from genetics

Clinical Science

Volumn 131, Issue 7, 2017, Pages 515-531

  Tan, Rhea ^a   Traylor, Matthew ^b   Rutten Jacobs, Loes ^a   Markus, Hugh ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b GUY S HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN; SCLEROPROTEIN;

ARTICLE; AUTOPSY; AUTOREGULATION; BIOCHEMICAL ANALYSIS; BLOOD BRAIN BARRIER; BRAIN BLOOD FLOW; CADASIL; CEREBROVASCULAR ACCIDENT; CEREBROVASCULAR DISEASE; EXTRACELLULAR MATRIX; GENE MUTATION; GENETIC ANALYSIS; GENOME-WIDE ASSOCIATION STUDY; HERITABILITY; HUMAN; LACUNAR STROKE; MONOGENIC DISORDER; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEOMICS; WHITE MATTER; ALOPECIA; BRAIN INFARCTION; GENETIC PREDISPOSITION; GENETICS; LEUKOENCEPHALOPATHY; METABOLISM; PHYSIOLOGY; SPINE DISEASE;

ALOPECIA; BLOOD-BRAIN BARRIER; CADASIL; CEREBRAL INFARCTION; CEREBRAL SMALL VESSEL DISEASES; COLLAGEN; EXTRACELLULAR MATRIX; EXTRACELLULAR MATRIX PROTEINS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LEUKOENCEPHALOPATHIES; SPINAL DISEASES;

EID: 85016411300     PISSN: 01435221     EISSN: 14708736     Source Type: Journal    
DOI: 10.1042/CS20160825     Document Type: Article

References (97)

1. Pantoni, L. (2014) Cerebral Small Vessel Disease, p. 371, Cambridge University Press, Cambridge.
2. Wardlaw, J. M., Smith, E. E., Biessels, G. J., Cordonnier, C., Fazekas, F., Frayne, R. et al. (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet. Neurol. 12, 822-838.
3. Caplan, L. R. (2015) Lacunar infarction and small vessel disease: pathology and pathophysiology. J. Stroke 17, 2-6.
4. Markus, H. S., Lythgoe, D. J., Ostegaard, L., O'Sullivan, M. and Williams, S. C. (2000) Reduced cerebral blood flow in white matter in ischaemic leukoaraiosis demonstrated using quantitative exogenous contrast based perfusion MRI. J. Neurol. Neurosurg. Psychiatry 69, 48-53.
5. Markus, H. S., Hunt, B., Palmer, K., Enzinger, C., Schmidt, H. and Schmidt, R. (2005) Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke 36, 1410-1414.
6. Wardlaw, J. M., Smith, C. and Dichgans, M. (2013) Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 12, 483-497.
7. Wardlaw, J. M., Sandercock, PAG, Dennis, M. S. and Starr, J. (2003) Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?. Stroke 34, 806-812.
8. Alafuzoff, I., Adolfsson, R., Grundke-Iqbal, I. and Winblad, B. (1985) Perivascular deposits of serum proteins in cerebral cortex in vascular dementia. Acta Neuropathol. 66, 292-298.
9. Poggesi, A., Pasi, M., Pescini, F., Pantoni, L. and Inzitari, D. (2016) Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J. Cereb. Blood Flow Metab. 36, 72-94.
10. Strand, T., Alling, C., Karlsson, B., Karlsson, I. and Winblad, B. (2016) Brain and plasma proteins in spinal fluid as markers for brain damage and severity of stroke. Stroke 15, 138-144.
11. Heye, A. K., Culling, R. D., Valdés Herná ndez, M. D. C., Thrippleton, M. J. and Wardlaw, J. M. (2014) Assessment of blood-brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review. NeuroImage Clin. 6, 262-274.
12. Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P. et al. (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383, 707-710.
13. Hara, K., Shiga, A., Fukutake, T., Nozaki, H., Miyashita, A., Yokoseki, A. et al. (2009) Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N. Engl. J. Med. 360, 1729-1739.
14. Verdura, E., Hervé, D., Scharrer, E., Amador, M. D. M., Guyant-Maré chal, L., Philippi, A. et al. (2015) Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 138, 2347-2358.
15. Nozaki, H., Kato, T., Nihonmatsu, M., Saito, Y., Mizuta, I., Noda, T. et al. (2016) Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. Neurology 86, 1964-1974.
16. Jerrard-Dunne, P., Cloud, G., Hassan, A. and Markus, H. S. (2003) Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke 34, 1364-1369.
17. Traylor, M., Bevan, S., Baron, J-C, Hassan, A., Lewis, C. M. and Markus, H. S. (2015) Genetic architecture of lacunar stroke. Stroke 46, 2407-2412.
18. Domenga, V., Fardoux, P., Lacombe, P., Monet, M., Maciazek, J., Krebs, L. T. et al. (2004) Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 18, 2730-3735.
19. Rutten, J. W., Haan, J., Terwindt, G. M., van Duinen, S. G., Boon, E. M. J. and Lesnik Oberstein, S. A. J. (2014) Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev. Mol. Diagn. 14, 593-603.
20. Joutel, A., Andreux, F., Gaulis, S., Domenga, V., Cecillon, M., Battail, N. et al. (2000) The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J. Clin. Invest. 105, 597-605.
21. Oka, C., Tsujimoto, R., Kajikawa, M., Koshiba-Takeuchi, K., Ina, J., Yano, M. et al. (2004) HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins. Development 131, 1041-1053.
22. Rhodes, J. M. and Simons, M. (2007) The extracellular matrix and blood vessel formation: not just a scaffold. J. Cell Mol. Med. 11, 176-205.
23. Alamowitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Van Agtmael, T. et al. (2009) Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology 73, 1873-1882.
24. Verbeek, E., Meuwissen, M. E. C., Verheijen, F. W., Govaert, P. P., Licht, D. J., Kuo, D. S. et al. (2012) COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur. J. Hum. Genet. 20, 844-851.
25. Vahedi, K. and Alamowitch, S. (2011) Clinical spectrum of type IV collagen (COL4A1) mutations: a novel genetic multisystem disease. Curr. Opin. Neurol. 24, 63-68.
26. Jeanne, M., Labelle-Dumais, C., Jorgensen, J., Kauffman, W. B., Mancini, G. M., Favor, J. et al. (2012) COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke. Am. J. Hum. Genet. 90, 91-101.
27. Gould, D. B., Phalan, F. C., van Mil, S. E., Sundberg, J. P., Vahedi, K., Massin, P. et al. (2006) Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N. Engl. J. Med. 354, 1489-1496.
28. Murray, L. S., Lu, Y., Taggart, A., Van Regemorter, N., Vilain, C., Abramowicz, M. et al. (2014) Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke. Hum. Mol. Genet. 23, 283-292.
29. Gould, D. B., Marchant, J. K., Savinova, O V, Smith, R. S. and John, S. W. M. (2007) Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis. Hum. Mol. Genet. 16, 798-807.
30. Kavanagh, D., Spitzer, D., Kothari, P. H., Shaikh, A., Liszewski, M. K., Richards, A. et al. (2008) New roles for the major human 3_-5_ exonuclease TREX1 in human disease. Cell Cycle 7, 1718-1725.
31. Richards, A., AMJM, van den Maagdenberg, Jen, J. C., Kavanagh, D., Bertram, P., Spitzer, D. et al. (2007) C-terminal truncations in human 3_-5_ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat. Genet. 39, 1068-1670.
32. DiFrancesco, J. C., Novara, F., Zuffardi, O., Forlino, A., Gioia, R., Cossu, F. et al. (2015) TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy. Neurol. Sci. 36, 323-330.
33. Seo, S., Singh, H. P., Lacal, P. M., Sasman, A., Fatima, A., Liu, T. et al. (2012) Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth. Proc. Natl. Acad. Sci. U. S. A. 109, 2015-2020.
34. Belmonte, JCI, Ryan, A. K., Blumberg, B., Rodriguez-Esteban, C., Yonei-Tamura, S., Tamura, K. et al. (1998) Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 394, 545-551.
35. Cellini, E., Disciglio, V., Novara, F., Barkovich, J. A., Mencarelli, M. A., Hayek, J. et al. (2012) Periventricular heterotopia with white matter abnormalities associated with 6p25 deletion. Am. J. Med. Genet 158, 1793-1797, A.
36. French, C. R., Seshadri, S., Destefano, A. L., Fornage, M., Arnold, C. R., Gage, P. J. et al. (2014) Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease. J. Clin. Invest. 124, 4877-4881.
37. Siegenthaler, J. A., Choe, Y., Patterson, K. P., Hsieh, I., Li, D., Jaminet, S.-C. et al. (2013) Foxc1 is required by pericytes during fetal brain angiogenesis. Biol. Open 2, 647-659.
38. Frantz, C., Stewart, K. M. and Weaver, V. M. (2010) The extracellular matrix at a glance. J. Cell Sci. 123, 4195-41200, Pt 24.
39. Naba, A., Clauser, K. R., Hoersch, S., Liu, H., Carr, S. A. and Hynes, R. O. (2012), The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell Proteomics 11, M111. 014647
40. Xu, J. and Shi, G.-P. (2014) Vascular wall extracellular matrix proteins and vascular diseases. Biochim. Biophys. Acta 1842, 2106-2119.
41. Joutel, A., Haddad, I., Ratelade, J. and Nelson, M. T. (2016) Perturbations of the cerebrovascular matrisome: a convergent mechanism in small vessel disease of the brain? J. Cereb. Blood Flow Metab. 36, 143-157.
42. Monet-Leprêtre, M., Haddad, I., Baron-Menguy, C., Fouillot-Panchal, M., Riani, M., Domenga-Denier, V. et al. (2013) Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. Brain 136(Pt 6), 1830-1845.
43. Dabertrand, F., Krøigaard, C., Bonev, A. D., Cognat, E., Dalsgaard, T., Domenga-Denier, V. et al. (2015) Potassium channelopathy-like defect underlies early-stage cerebrovascular dysfunction in a genetic model of small vessel disease. Proc. Natl. Acad. Sci. U. S. A. 112, E796-F805.
44. Capone, C., Dabertrand, F., Baron-Menguy, C., Chalaris, A., Ghezali, L., Domenga-Denier, V. et al. (2016) Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. Elife 5, e17536.
45. Capone, C., Cognat, E., Ghezali, L., Baron-Menguy, C., Aubin, D., Mesnard, L. et al. (2016) Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice. Ann. Neurol. 79, 387-403.
46. Walsh, J. S., Perniciaro, C. and Meschia, J. F. (2000) CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): diagnostic skin biopsy changes determined by electron microscopy. J. Am. Acad. Dermatol. 43, 1125-1127.
47. Monet, M., Domenga, V., Lemaire, B., Souilhol, C., Langa, F., Babinet, C. et al. (2007) The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo. Hum. Mol. Genet. 16, 982-992.
48. Dabertrand, F., Krøigaard, C., Bonev, A. D., Cognat, E., Dalsgaard, T., Domenga-Denier, V. et al. (2015) Potassium channelopathy-like defect underlies early-stage cerebrovascular dysfunction in a genetic model of small vessel disease. Proc. Natl. Acad. Sci. U. S. A. 112, E796-E805.
49. Joutel, A., Monet-Leprêtre, M., Gosele, C., Baron-Menguy, C., Hammes, A., Schmidt, S. et al. (2010) Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J. Clin. Invest. 120, 433-445.
50. Kast, J., Hanecker, P., Beaufort, N., Giese, A., Joutel, A., Dichgans, M. et al. (2014) Sequestration of latent TGF-B binding protein 1 into CADASIL-related Notch3-ECD deposits. Acta Neuropathol. Commun. 2, 96.
51. Liem, M. K., Lesnik Oberstein, SAJ, Haan, J., Boom, R v d, Ferrari, M. D., Buchem, M. A. and Grond, J. V. (2009) Cerebrovascular reactivity is a main determinant of white matter hyperintensity progression in CADASIL. AJNR Am. J. Neuroradiol. 30, 1244-1247.
52. Lacombe, P., Oligo, C., Domenga, V., Tournier-Lasserve, E. and Joutel, A. (2005) Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke 36, 1053-1058.
53. Edwards, D. R., Handsley, M. M. and Pennington, C. J. (2008) The ADAM metalloproteinases. Mol. Aspects Med. 29, 258-289.
54. Koide, M., Penar, P. L., Tranmer, B. I. and Wellman, G. C. (2007) Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes. Am. J. Physiol. Heart Circ. Physiol. 293, H1750-H1759.
55. Jucker, M. and Walker, L. C. (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45-51.
56. Prusiner, S. B. (2013) Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601-623.
57. Meng, H., Zhang, X., Hankenson, K. D. and Wang, M. M. (2009) Thrombospondin 2 potentiates notch3/jagged1 signaling. J. Biol. Chem. 284, 7866-7874.
58. Bornstein, P., Kyriakides, T. R., Yang, Z., Armstrong, L. C. and Birk, D. E. (2000) Thrombospondin 2 modulates collagen fibrillogenesis and angiogenesis. J. Investig. Dermatol. Symp. Proc. 5, 61-66.
59. Calabro, N. E., Kristofik, N. J. and Kyriakides, T. R. (2014) Thrombospondin-2 and extracellular matrix assembly. Biochim. Biophys. Acta 1840, 2396-2402.
60. Duering, M., Karpinska, A., Rosner, S., Hopfner, F., Zechmeister, M., Peters, N. et al. (2011) Co-aggregate formation of CADASIL-mutant NOTCH3: a single-particle analysis. Hum. Mol. Genet. 20, 3256-3265.
61. Hyytiäinen, M., Penttinen, C. and Keski-Oja, J. (2004) Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit. Rev. Clin. Lab. Sci. 41, 233-264.
62. Beaufort, N., Scharrer, E., Kremmer, E., Lux, V., Ehrmann, M., Huber, R. et al. (2014) Cerebral small vessel disease-related protease HtrA1 processes latent TGF-B binding protein 1 and facilitates TGF-B signaling. Proc. Natl. Acad. Sci. U. S. A. 111, 16496-16501.
63. Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M. et al. (2003) A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat. Med. 9, 407-415.
64. Preissner, K. T. and Reuning, U. (2011) Vitronectin in vascular context: facets of a multitalented matricellular protein. Semin. Thromb. Hemost. 37, 408-424.
65. Oide, T., Nakayama, H., Yanagawa, S., Ito, N., Ikeda, S.-I. and Arima, K. (2008) Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Neuropathology 28, 132-142.
66. Arima, K., Yanagawa, S., Ito, N. and Ikeda, S. (2003) Cerebral arterial pathology of CADASIL and CARASIL (Maeda syndrome). Neuropathology 23, 327-334.
67. Schmidt, H., Zeginigg, M., Wiltgen, M., Freudenberger, P., Petrovic, K., Cavalieri, M. et al. (2011) Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. Brain 134(Pt 11), 3384-3397.
68. Rutten-Jacobs, LCA, Traylor, M, Adib-Samii, P., Thijs, V., Sudlow, C., Rothwell, P. M. et al. (2015) Common NOTCH3 variants and cerebral small-vessel disease. Stroke 46, 1482-1487.
69. Breedveld, G., de Coo, I. F., Lequin, M. H., Arts, WFM, Heutink, P., Gould, D. B. et al. (2006) Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J. Med. Genet. 43, 490-495.
70. Plaisier, E., Chen, Z., Gekeler, F., Benhassine, S., Dahan, K., Marro, B. et al. (2010) Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Am. J. Med. Genet. 152, 2550-2555, A.
71. Rannikmäe, K., Davies, G., Thomson, P. A., Bevan, S., Devan, W. J., Falcone, G. J. et al. (2015) Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology 84, 918-926.
72. Traylor, M., Zhang, C. R., Adib-Samii, P., Devan, W. J., Parsons, O. E., Lanfranconi, S. et al. (2016) Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke. Neurology 86, 146-153.
73. Tümer, Z. and Bach-Holm, D. (2009) Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. Eur. J. Hum. Genet. 17, 1527-1539.
74. Siegenthaler, J. A., Choe, Y., Patterson, K. P., Hsieh, I., Li, D., Jaminet, S.-C. et al. (2013) Foxc1 is required by pericytes during fetal brain angiogenesis. Biol. Open 2, 647-659.
75. Johnston, S., Mendis, S., Mathers, C., Falcone, G., Malik, R., Dichgans, M. et al. (2016) Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet. Neurol. 15, 695-707.
76. Reyahi, A., Nik, A. M., Ghiami, M., Gritli-Linde, A., Ponté n, F., Johansson, B. R. et al. (2015) Foxf2 is required for brain pericyte differentiation and development and maintenance of the blood-brain barrier. Dev. Cell 34, 19-32.
77. McKeone, R., Vieira, H., Gregory-Evans, K., Gregory-Evans, C. Y. and Denny, P. (2011) Foxf2: a novel locus for anterior segment dysgenesis adjacent to the Foxc1 gene. PLoS One 6, e25489.
78. Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (2016) Stroke Genetics Network (SiGN), International Stroke Genetics Consortium (ISGC). Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 15, 695-707.
79. Dziewulska, D. and Lewandowska, E. (2012) Pericytes as a new target for pathological processes in CADASIL. Neuropathology 32, 515-521.
80. Gu, X., Liu, X.-Y., Fagan, A., Gonzalez-Toledo, M. E. and Zhao, L.-R. (2012) Ultrastructural changes in cerebral capillary pericytes in aged Notch3 mutant transgenic mice. Ultrastruct Pathol. 36, 48-55.
81. Ghosh, M., Balbi, M., Hellal, F., Dichgans, M., Lindauer, U. and Plesnila, N. (2015) Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann. Neurol. 78, 887-900.
82. Rustenhoven, J., Aalderink, M., Scotter, E. L., Oldfield, R. L., Bergin, P. S., Mee, E. W. et al. (2016) TGF-beta1 regulates human brain pericyte inflammatory processes involved in neurovasculature function. J. Neuroinflammation 13, 37.
83. Miyazaki, T., Kim, Y-S, Yoon, J., Wang, H., Suzuki, T., Morse, H. C. et al. (2014) The 3_-5_ DNA exonuclease TREX1 directly interacts with poly(ADP-ribose) polymerase-1 (PARP1) during the DNA damage response. J. Biol. Chem. 289, 32548-32558.
84. Adib-Samii, P., Devan, W., Traylor, M., Lanfranconi, S., Zhang, C. R., Cloonan, L. et al. (2015) Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke. Stroke 46, 348-353.
85. Holliday, E. G., Traylor, M., Malik, R., Bevan, S., Falcone, G., Hopewell, J. C. et al. (2015) Genetic overlap between diagnostic subtypes of ischemic stroke. Stroke 46, 615-619.
86. Verhaaren, BFJ, Debette, S., Bis, J. C., Smith, J. A., Ikram, M. K., Adams, H. H. et al. (2015) Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. Circ. Cardiovasc. Genet. 8, 398-409
87. Traylor, M., Malik, R., Nalls, M. A., Cotlarciuc, I., Radmanesh, F., Thorleifsson, G. et al. (2016), Genetic variation at 16q24. 2 is associated with small vessel stroke. Ann. Neurol., doi: 10. 1002/ana. 24840
88. Teider, N., Scott, D. K., Neiss, A., Weeraratne, S. D., Amani, V. M., Wang, Y. et al. (2010) Neuralized1 causes apoptosis and downregulates Notch target genes in medulloblastoma. Neuro Oncol. 12, 1244-1256
89. Koutelou, E., Sato, S., Tomomori-Sato, C., Florens, L., Swanson, S. K., Washburn, M. P. et al. (2008) Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1. J. Biol. Chem. 283, 3846-3853.
90. Traylor, M., Rutten-Jacobs, L. C. A., Thijs, V., Holliday, E. G., Levi, C., Bevan, S. et al. (2016) Genetic associations with white matter hyperintensities confer risk of lacunar stroke. Stroke 47, 1174-1179.
91. Woo, D., Falcone, G. J., Devan, W. J., Brown, W. M., Biffi, A., Howard, T. D. et al. (2014) Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am. J. Hum. Genet. 94, 511-521.
92. Habashi, J. P., Judge, D. P., Holm, T. M., Cohn, R. D., Loeys, B. L., Cooper, T. K. et al. (2016) Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117-121.
93. Ross, O. A., Soto-Ortolaza, A. I., Heckman, M. G., Verbeeck, C., Serie, D. J., Rayaprolu, S. et al. (2013) NOTCH3 variants and risk of ischemic stroke. PLoS One 8, e75035
94. Dong, Y., Hassan, A., Zhang, Z., Huber, D., Dalageorgou, C., Markus, H. S. et al. (2002) Yield of Screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke 34, 203-206.
95. Ito, D. (2002) Notch3 gene polymorphism and ischaemic cerebrovascular disease. J. Neurol. Neurosurg. Psychiatry 72, 382-384.
96. Wang, T., Sharma, S. D., Fox, N., Rossor, M., Brown, M. J. and Sharma, P. (2000) Description of a simple test for CADASIL disease and determination of mutation frequencies in sporadic ischaemic stroke and dementia patients. J. Neurol. Neurosurg. Psychiatry 69, 652-654.
97. Weng, Y.-C., Sonni, A., Labelle-Dumais, C., de Leau, M., Kauffman, W. B., Jeanne, M. et al. (2012) COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage. Ann. Neurol. 71, 470-477.