Skip to main content
NCBI home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2005 Sep;76(9):1242–1248. doi: 10.1136/jnnp.2004.051854

Functional analysis of a recurrent missense mutation in Notch3 in CADASIL

T Haritunians 1, T Chow 1, R P J De Lange 1, J Nichols 1, D Ghavimi 1, N Dorrani 1, C St 1, G Weinmaster 1, C Schanen 1
PMCID: PMC1739793  PMID: 16107360

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular dementia characterised by recurrent ischemic strokes in the deep white matter. Mutations in the gene encoding the cell surface receptor, Notch3, have been identified in CADASIL patients, and accumulation of the extracellular domain of Notch3 has been demonstrated in affected vessels. Almost all CADASIL mutations alter the number of cysteine residues in the epidermal growth factor (EGF)-like repeats in the extracellular domain of the protein.

Objectives: To understand the functional consequences of a recurrent CADASIL mutation on furin processing, cell surface expression, ligand binding, and activation of a downstream effector CBF1 by the Notch3 receptor.

Methods: We expressed wild type and mutant Notch3 receptors in cultured cells and examined cell surface expression of the proteins. We also applied a new flow cytometry based approach to semi-quantitatively measure binding to three Notch ligands. Additionally, we used a well characterised co-culture system to examine ligand dependent activation of transcription from a CBF1-luciferase reporter construct.

Results: These studies revealed subtle abnormalities in furin processing of the mutant receptor, although both heterodimeric and full length receptors are present on the cell surface, are capable of interacting with soluble forms of three ligands, Delta1, Delta4, and Jagged1, and retain the ability to activate CBF1 in a ligand dependent manner.

Conclusions: By comparison with other mutant forms of Notch3, these data indicate that individual CADASIL mutations can have disparate effects on Notch3 expression and function.

Full Text

The Full Text of this article is available as a PDF (117.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auer D. P., Pütz B., Gössl C., Elbel G., Gasser T., Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology. 2001 Feb;218(2):443–451. doi: 10.1148/radiology.218.2.r01fe24443. [DOI] [PubMed] [Google Scholar]
  2. Brou C., Logeat F., Gupta N., Bessia C., LeBail O., Doedens J. R., Cumano A., Roux P., Black R. A., Israël A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000 Feb;5(2):207–216. doi: 10.1016/s1097-2765(00)80417-7. [DOI] [PubMed] [Google Scholar]
  3. Bush G., diSibio G., Miyamoto A., Denault J. B., Leduc R., Weinmaster G. Ligand-induced signaling in the absence of furin processing of Notch1. Dev Biol. 2001 Jan 15;229(2):494–502. doi: 10.1006/dbio.2000.9992. [DOI] [PubMed] [Google Scholar]
  4. Campos Alexandre H., Wang Wenli, Pollman Matthew J., Gibbons Gary H. Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ Res. 2002 Nov 29;91(11):999–1006. doi: 10.1161/01.res.0000044944.99984.25. [DOI] [PubMed] [Google Scholar]
  5. Chabriat H., Vahedi K., Iba-Zizen M. T., Joutel A., Nibbio A., Nagy T. G., Krebs M. O., Julien J., Dubois B., Ducrocq X. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet. 1995 Oct 7;346(8980):934–939. doi: 10.1016/s0140-6736(95)91557-5. [DOI] [PubMed] [Google Scholar]
  6. De Strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., Schroeter E. H., Schrijvers V., Wolfe M. S., Ray W. J. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518–522. doi: 10.1038/19083. [DOI] [PubMed] [Google Scholar]
  7. Dichgans M., Ludwig H., Müller-Höcker J., Messerschmidt A., Gasser T. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280–285. doi: 10.1038/sj.ejhg.5200460. [DOI] [PubMed] [Google Scholar]
  8. Domenga Valérie, Fardoux Peggy, Lacombe Pierre, Monet Marie, Maciazek Jacqueline, Krebs Luke T., Klonjkowski Bernard, Berrou Eliane, Mericskay Matthias, Li Zhen. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 2004 Nov 15;18(22):2730–2735. doi: 10.1101/gad.308904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Donahue Christine P., Kosik Kenneth S. Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics. 2004 Jan;83(1):59–65. doi: 10.1016/s0888-7543(03)00206-4. [DOI] [PubMed] [Google Scholar]
  10. Fortini M. E., Artavanis-Tsakonas S. The suppressor of hairless protein participates in notch receptor signaling. Cell. 1994 Oct 21;79(2):273–282. doi: 10.1016/0092-8674(94)90196-1. [DOI] [PubMed] [Google Scholar]
  11. Goate A. M., Morris J. C. Notch3 mutations and the potential for diagnostic testing for CADASIL. Lancet. 1997 Nov 22;350(9090):1490–1490. doi: 10.1016/S0140-6736(97)22047-7. [DOI] [PubMed] [Google Scholar]
  12. Haritunians Talin, Boulter Jim, Hicks Carol, Buhrman Jonathon, DiSibio Guy, Shawber Carrie, Weinmaster Gerry, Nofziger Donna, Schanen Carolyn. CADASIL Notch3 mutant proteins localize to the cell surface and bind ligand. Circ Res. 2002 Mar 22;90(5):506–508. doi: 10.1161/01.res.0000013796.73742.c8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hicks C., Johnston S. H., diSibio G., Collazo A., Vogt T. F., Weinmaster G. Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nat Cell Biol. 2000 Aug;2(8):515–520. doi: 10.1038/35019553. [DOI] [PubMed] [Google Scholar]
  14. Hicks Carol, Ladi Ena, Lindsell Claire, Hsieh James J-D, Hayward S. Diane, Collazo Andres, Weinmaster Gerry. A secreted Delta1-Fc fusion protein functions both as an activator and inhibitor of Notch1 signaling. J Neurosci Res. 2002 Jun 15;68(6):655–667. doi: 10.1002/jnr.10263. [DOI] [PubMed] [Google Scholar]
  15. Hsieh J. J., Henkel T., Salmon P., Robey E., Peterson M. G., Hayward S. D. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol. 1996 Mar;16(3):952–959. doi: 10.1128/mcb.16.3.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hussain Monira B., Singhal Sumeet, Markus Hugh S., Singer Donald R. J. Abnormal vasoconstrictor responses to angiotensin II and noradrenaline in isolated small arteries from patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Stroke. 2004 Mar 4;35(4):853–858. doi: 10.1161/01.STR.0000120730.54282.A0. [DOI] [PubMed] [Google Scholar]
  17. Iso Tatsuya, Hamamori Yasuo, Kedes Larry. Notch signaling in vascular development. Arterioscler Thromb Vasc Biol. 2003 Feb 13;23(4):543–553. doi: 10.1161/01.ATV.0000060892.81529.8F. [DOI] [PubMed] [Google Scholar]
  18. Jarriault S., Brou C., Logeat F., Schroeter E. H., Kopan R., Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995 Sep 28;377(6547):355–358. doi: 10.1038/377355a0. [DOI] [PubMed] [Google Scholar]
  19. Jarriault S., Le Bail O., Hirsinger E., Pourquié O., Logeat F., Strong C. F., Brou C., Seidah N. G., Isra l A. Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol Cell Biol. 1998 Dec;18(12):7423–7431. doi: 10.1128/mcb.18.12.7423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Joutel A., Andreux F., Gaulis S., Domenga V., Cecillon M., Battail N., Piga N., Chapon F., Godfrain C., Tournier-Lasserve E. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest. 2000 Mar;105(5):597–605. doi: 10.1172/JCI8047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Joutel A., Corpechot C., Ducros A., Vahedi K., Chabriat H., Mouton P., Alamowitch S., Domenga V., Cécillion M., Marechal E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996 Oct 24;383(6602):707–710. doi: 10.1038/383707a0. [DOI] [PubMed] [Google Scholar]
  22. Joutel A., Vahedi K., Corpechot C., Troesch A., Chabriat H., Vayssière C., Cruaud C., Maciazek J., Weissenbach J., Bousser M. G. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511–1515. doi: 10.1016/S0140-6736(97)08083-5. [DOI] [PubMed] [Google Scholar]
  23. Joutel Anne, Monet Marie, Domenga Valérie, Riant Florence, Tournier-Lasserve Elisabeth. Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling Pathway. Am J Hum Genet. 2004 Jan 8;74(2):338–347. doi: 10.1086/381506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Karlström Helena, Beatus Paul, Dannaeus Karin, Chapman Gavin, Lendahl Urban, Lundkvist Johan. A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. Proc Natl Acad Sci U S A. 2002 Dec 13;99(26):17119–17124. doi: 10.1073/pnas.252624099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kopan R., Nye J. S., Weintraub H. The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development. 1994 Sep;120(9):2385–2396. doi: 10.1242/dev.120.9.2385. [DOI] [PubMed] [Google Scholar]
  26. Kotorii S., Takahashi K., Kamimura K., Nishio T., Arima K., Yamada H., Uyama E., Uchino M., Suenaga A., Matsumoto M. Mutations of the notch3 gene in non-caucasian patients with suspected CADASIL syndrome. Dement Geriatr Cogn Disord. 2001 May-Jun;12(3):185–193. doi: 10.1159/000051256. [DOI] [PubMed] [Google Scholar]
  27. Lawrence N., Klein T., Brennan K., Martinez Arias A. Structural requirements for notch signalling with delta and serrate during the development and patterning of the wing disc of Drosophila. Development. 2000 Jul;127(14):3185–3195. doi: 10.1242/dev.127.14.3185. [DOI] [PubMed] [Google Scholar]
  28. Lindner V., Booth C., Prudovsky I., Small D., Maciag T., Liaw L. Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cell matrix and cell-cell interaction. Am J Pathol. 2001 Sep;159(3):875–883. doi: 10.1016/S0002-9440(10)61763-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lindsell C. E., Boulter J., diSibio G., Gossler A., Weinmaster G. Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development. Mol Cell Neurosci. 1996;8(1):14–27. doi: 10.1006/mcne.1996.0040. [DOI] [PubMed] [Google Scholar]
  30. Lindsell C. E., Shawber C. J., Boulter J., Weinmaster G. Jagged: a mammalian ligand that activates Notch1. Cell. 1995 Mar 24;80(6):909–917. doi: 10.1016/0092-8674(95)90294-5. [DOI] [PubMed] [Google Scholar]
  31. Logeat F., Bessia C., Brou C., LeBail O., Jarriault S., Seidah N. G., Israël A. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8108–8112. doi: 10.1073/pnas.95.14.8108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lu F. M., Lux S. E. Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5663–5667. doi: 10.1073/pnas.93.11.5663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Manabe Y., Murakami T., Iwatsuki K., Narai H., Warita H., Hayashi T., Shoji M., Imai Y., Abe K. Nocturnal blood pressure dip in CADASIL. J Neurol Sci. 2001 Dec 15;193(1):13–16. doi: 10.1016/s0022-510x(01)00636-0. [DOI] [PubMed] [Google Scholar]
  34. Mizushima S., Nagata S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 1990 Sep 11;18(17):5322–5322. doi: 10.1093/nar/18.17.5322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mizutani T., Taniguchi Y., Aoki T., Hashimoto N., Honjo T. Conservation of the biochemical mechanisms of signal transduction among mammalian Notch family members. Proc Natl Acad Sci U S A. 2001 Jul 17;98(16):9026–9031. doi: 10.1073/pnas.161269998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Morrison S. J., Perez S. E., Qiao Z., Verdi J. M., Hicks C., Weinmaster G., Anderson D. J. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell. 2000 May 26;101(5):499–510. doi: 10.1016/s0092-8674(00)80860-0. [DOI] [PubMed] [Google Scholar]
  37. Morrissette J. D., Colliton R. P., Spinner N. B. Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet. 2001 Feb 15;10(4):405–413. doi: 10.1093/hmg/10.4.405. [DOI] [PubMed] [Google Scholar]
  38. Mumm J. S., Schroeter E. H., Saxena M. T., Griesemer A., Tian X., Pan D. J., Ray W. J., Kopan R. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell. 2000 Feb;5(2):197–206. doi: 10.1016/s1097-2765(00)80416-5. [DOI] [PubMed] [Google Scholar]
  39. Nofziger D., Miyamoto A., Lyons K. M., Weinmaster G. Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts. Development. 1999 Apr;126(8):1689–1702. doi: 10.1242/dev.126.8.1689. [DOI] [PubMed] [Google Scholar]
  40. Nye J. S., Kopan R., Axel R. An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells. Development. 1994 Sep;120(9):2421–2430. doi: 10.1242/dev.120.9.2421. [DOI] [PubMed] [Google Scholar]
  41. Peters Nils, Opherk Christian, Zacherle Simone, Capell Anja, Gempel Petra, Dichgans Martin. CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Exp Cell Res. 2004 Oct 1;299(2):454–464. doi: 10.1016/j.yexcr.2004.06.004. [DOI] [PubMed] [Google Scholar]
  42. Rand M. D., Grimm L. M., Artavanis-Tsakonas S., Patriub V., Blacklow S. C., Sklar J., Aster J. C. Calcium depletion dissociates and activates heterodimeric notch receptors. Mol Cell Biol. 2000 Mar;20(5):1825–1835. doi: 10.1128/mcb.20.5.1825-1835.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ray W. J., Yao M., Mumm J., Schroeter E. H., Saftig P., Wolfe M., Selkoe D. J., Kopan R., Goate A. M. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem. 1999 Dec 17;274(51):36801–36807. doi: 10.1074/jbc.274.51.36801. [DOI] [PubMed] [Google Scholar]
  44. Ray W. J., Yao M., Nowotny P., Mumm J., Zhang W., Wu J. Y., Kopan R., Goate A. M. Evidence for a physical interaction between presenilin and Notch. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3263–3268. doi: 10.1073/pnas.96.6.3263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rebay I., Fleming R. J., Fehon R. G., Cherbas L., Cherbas P., Artavanis-Tsakonas S. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell. 1991 Nov 15;67(4):687–699. doi: 10.1016/0092-8674(91)90064-6. [DOI] [PubMed] [Google Scholar]
  46. Ross D. A., Kadesch T. The notch intracellular domain can function as a coactivator for LEF-1. Mol Cell Biol. 2001 Nov;21(22):7537–7544. doi: 10.1128/MCB.21.22.7537-7544.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Ross David A., Rao Prakash K., Kadesch Tom. Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Mol Cell Biol. 2004 Apr;24(8):3505–3513. doi: 10.1128/MCB.24.8.3505-3513.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ruchoux M. M., Chabriat H., Bousser M. G., Baudrimont M., Tournier-Lasserve E. Presence of ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL. Stroke. 1994 Nov;25(11):2291–2292. doi: 10.1161/01.str.25.11.2291. [DOI] [PubMed] [Google Scholar]
  49. Ruchoux M. M., Guerouaou D., Vandenhaute B., Pruvo J. P., Vermersch P., Leys D. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropathol. 1995;89(6):500–512. doi: 10.1007/BF00571504. [DOI] [PubMed] [Google Scholar]
  50. Ruchoux Marie Magdeleine, Domenga Valérie, Brulin Peggy, Maciazek Jacqueline, Limol Sylvie, Tournier-Lasserve Elisabeth, Joutel Anne. Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol. 2003 Jan;162(1):329–342. doi: 10.1016/S0002-9440(10)63824-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Schrijver I., Liu W., Brenn T., Furthmayr H., Francke U. Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet. 1999 Oct;65(4):1007–1020. doi: 10.1086/302582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Schultz A., Santoianni R., Hewan-Lowe K. Vasculopathic changes of CADASIL can be focal in skin biopsies. Ultrastruct Pathol. 1999 Jul-Aug;23(4):241–247. doi: 10.1080/019131299281572. [DOI] [PubMed] [Google Scholar]
  53. Shimizu K., Chiba S., Saito T., Kumano K., Hirai H. Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors. Biochem Biophys Res Commun. 2000 Sep 16;276(1):385–389. doi: 10.1006/bbrc.2000.3469. [DOI] [PubMed] [Google Scholar]
  54. Shutter J. R., Scully S., Fan W., Richards W. G., Kitajewski J., Deblandre G. A., Kintner C. R., Stark K. L. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev. 2000 Jun 1;14(11):1313–1318. [PMC free article] [PubMed] [Google Scholar]
  55. Struhl G., Adachi A. Nuclear access and action of notch in vivo. Cell. 1998 May 15;93(4):649–660. doi: 10.1016/s0092-8674(00)81193-9. [DOI] [PubMed] [Google Scholar]
  56. Struhl G., Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature. 1999 Apr 8;398(6727):522–525. doi: 10.1038/19091. [DOI] [PubMed] [Google Scholar]
  57. Sweeney Catherine, Morrow David, Birney Yvonne A., Coyle Seamus, Hennessy Colm, Scheller Agnieszka, Cummins Philip M., Walls Dermot, Redmond Eileen M., Cahill Paul A. Notch 1 and 3 receptor signaling modulates vascular smooth muscle cell growth, apoptosis, and migration via a CBF-1/RBP-Jk dependent pathway. FASEB J. 2004 Jul 9;18(12):1421–1423. doi: 10.1096/fj.04-1700fje. [DOI] [PubMed] [Google Scholar]
  58. Tournier-Lasserve E., Iba-Zizen M. T., Romero N., Bousser M. G. Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy. Stroke. 1991 Oct;22(10):1297–1302. doi: 10.1161/01.str.22.10.1297. [DOI] [PubMed] [Google Scholar]
  59. Villa N., Walker L., Lindsell C. E., Gasson J., Iruela-Arispe M. L., Weinmaster G. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev. 2001 Oct;108(1-2):161–164. doi: 10.1016/s0925-4773(01)00469-5. [DOI] [PubMed] [Google Scholar]
  60. Wang S., Sdrulla A. D., diSibio G., Bush G., Nofziger D., Hicks C., Weinmaster G., Barres B. A. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron. 1998 Jul;21(1):63–75. doi: 10.1016/s0896-6273(00)80515-2. [DOI] [PubMed] [Google Scholar]
  61. Zimrin A. B., Pepper M. S., McMahon G. A., Nguyen F., Montesano R., Maciag T. An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J Biol Chem. 1996 Dec 20;271(51):32499–32502. doi: 10.1074/jbc.271.51.32499. [DOI] [PubMed] [Google Scholar]
  62. de Lange R. P., Bolt J., Reid E., da Silva R., Shaw D. J., St Clair D. M. Screening British CADASIL families for mutations in the NOTCH3 gene. J Med Genet. 2000 Mar;37(3):224–225. doi: 10.1136/jmg.37.3.224. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES