Neurological Surgery 脳神経外科40巻2号

2012年02月発行

総説

もやもや病関連遺伝子

著者： 小泉昭夫¹ 小林果¹ 人見敏明¹

所属機関： ¹京都大学大学院医学研究科環境衛生学分野

ページ範囲：P.105 - P.118

Ⅰ．はじめに

　もやもや病は，内頚動脈終末部の狭窄とその周辺で形成される異常な血管網を特徴とする疾患である．この疾患は，1957年に竹内，清水ら東京大学グループによって，内頚動脈に閉塞を認める疾患として初めて報告された⁵⁵⁾．1968年にはKudoら慶應義塾大学グループが内頚動脈閉塞を病理学的に証明した²⁸⁾．「もやもや病」という特徴的な病名は，Suzuki，Takakuら東北大学グループによる命名で，血管造影によって見える異常血管網が，タバコの煙のもやもやとたちのぼる様子に似ていることからきている．1969年に初めて「Moyamoya disease」の表現が論文⁵³⁾で用いられ，命名のユニークさから世界中で使われている．現在では，治療としてKarasawaら京都大学および国立循環器病研究センターのグループが1978年に開発した外科的療法²⁵⁾が行われ，有効な治療法として確立されている．

　もやもや病は，白人やアフリカ人では少なく，東アジアの日本，韓国および中国で頻度が高い疾患である．わが国では，約1万人に1人の頻度²⁹⁾であり，女性に多く，成人では脳出血や脳梗塞によって発症することで知られている¹²⁾．また約15％に家族歴が認められ，遺伝素因の関与が疑われてきた²⁹⁾．

　遺伝素因が強いことから，原因遺伝子の存在が想定され，2000年前後より本格的な遺伝子の探索が行われ，3p24-26 ¹⁸⁾，6q25 ²⁰⁾，8q23 ⁴⁹⁾および17q25.3 ⁶¹⁾が関与していることが報告された．その後，17q25.3については，2008年に15家系を用いた全ゲノム連鎖解析により確認された³⁷⁾．またこの領域はさらに検討され，2010年には，もやもや病患者の領域内の遺伝子Raptorに，一般人口では稀少な多型が高い頻度で見出されることが発見され，この多型と連鎖不平衡にあるハプロタイプに原因遺伝子が存在することが報告された³²⁾．その後，この領域にあるRNF213との高い相関が報告され^27,23)，最終的に厳密な検討によりRNF213が感受性遺伝子として同定された³³⁾．感受性遺伝子として同定されたことは，RNF213の変異に加えて何らかの他の要因の関与があることを示唆する．本稿では，頭蓋内血管の狭窄を伴う単一遺伝子疾患を含め，広くもやもや病ともやもや症候群，およびその関連遺伝子を概説する．同時に，共通項からもやもや病の感受性を高める要因についても考察を行う．

参考文献

1）Aicardi J, Goutieres F：A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15：49-54, 1984

2）Andeejani AM, Salih MA, Kolawole T, Gader AM, Malabarey TO, al Damegh S, al Boukai A：Moyamoya syndrome with unusual angiographic findings and protein C deficiency：review of the literature. J Neurol Sci 159：11-16, 1998

3）Bober MB, Khan N, Kaplan J, Lewis K, Feinstein JA, Scott CI Jr, Steinberg GK：Majewski osteodysplastic primordial dwarfism typeⅡ (MOPDⅡ)：expanding the vascular phenotype. Am J Med Genet A 152A：960-965, 2010

4）Boerkoel CF, Takashima H, John J, Yan J, Stankiewicz P, Rosenbarker L, Andre JL, Bogdanovic R, Burguet A, Cockfield S, Cordeiro I, Frund S, Illies F, Joseph M, Kaitila I, Lama G, Loirat C, McLeod DR, Milford DV, Petty EM, Rodrigo F, Saraiva JM, Schmidt B, Smith GC, Spranger J, Stein A, Thiele H, Tizard J, Weksberg R, Lupski JR, Stockton DW：Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat Genet 30：215-220, 2002

5）Bridgers WH：Cerebral vascular disease accompanying sickle cell anemia. Am J Pathol 15：353-362, 1939

6）Charuvanij A, Laothamatas J, Torcharus K, Sirivimonmas S：Moyamoya disease and protein S deficiency：a case report. Pediatr Neurol 17：171-173, 1997

7）Codd PJ, Scott RM, Smith ER：Seckel syndrome and moyamoya. J Neurosurg Pediatr 3：320-324, 2009

8）Crow YJ, Leitch A, Hayward BE, Garner A, Parmar R, Griffith E, Ali M, Semple C, Aicardi J, Babul-Hirji R, Baumann C, Baxter P, Bertini E, Chandler KE, Chitayat D, Cau D, Dery C, Fazzi E, Goizet C, King MD, Klepper J, Lacombe D, Lanzi G, Lyall H, Martinez-Frias ML, Mathieu M, McKeown C, Monier A, Oade Y, Quarrell OW, Rittey CD, Rogers RC, Sanchis A, Stephenson JB, Tacke U, Till M, Tolmie JL, Tomlin P, Voit T, Weschke B, Woods CG, Lebon P, Bonthron DT, Ponting CP, Jackson AP：Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat Genet 38：910-916, 2006

9）Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P, Bonthron DT, Jackson AP, Barnes DE, Lindahl T：Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet 38：917-920, 2006

10）Derbent M, Oncel Y, Tokel K, Varan B, Haberal A, Yazici AC, Legius E, Ozbek N：Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations. Am J Med Genet A 152A：2768-2774, 2010

11）Fatigati V, Murphy RA：Actin and tropomyosin variants in smooth muscles. Dependence on tissue type. J Biol Chem 259：14383-14388, 1984

12）Fukui M, Kono S, Sueishi K, Ikezaki K：Moyamoya disease. Neuropathology 20 (Suppl)：S61-64, 2000

13）Gelb BD, Tartaglia M：Noonan syndrome and related disorders：dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet 15 Spec No 2：R220-226, 2006

14）Goutières F, Aicardi J, Barth PG, Lebon P：Aicardi-Goutières syndrome：an update and results of interferon-alpha studies. Ann Neurol 44：900-907, 1998

15）Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH, Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, Marian AJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ, Veeraraghavan S, Muzny DM, Wheeler DA, Willerson JT, Yu RK, Shete SS, Scherer SE, Raman CS, Buja LM, Milewicz DM：Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet 84：617-627, 2009

16）Hinnant CA：Thromboembolic infarcts occurring after mild traumatic brain injury in a paediatric patient with Noonan's syndrome. Brain Inj 8：719-727, 1994

17）Hung PC, Wang HS, Wong AM：Moyamoya syndrome in a child with Noonan syndrome. Pediatr Neurol 45：129-131, 2011

18）Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T：Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 64：533-537, 1999

19）Inoue H, Yamanaka S：The use of induced pluripotent stem cells in drug development. Clin Pharmacol Ther 89：655-661, 2011

20）Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M：Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 15：179-182, 2000

21）Jabbour R, Taher A, Shamseddine A, Atweh SF：Moyamoya syndrome with intraventricular hemorrhage in an adult with factor V Leiden mutation. Arch Neurol 62：1144-1146, 2005

22）Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E, Bicknell LS, Kayserili H, Li Y, Tuysuz B, Nurnberg G, Kiess W, Koegl M, Baessmann I, Buruk K, Toraman B, Kayipmaz S, Kul S, Ikbal M, Turner DJ, Taylor MS, Aerts J, Scott C, Milstein K, Dollfus H, Wieczorek D, Brunner HG, Hurles M, Jackson AP, Rauch A, Nurnberg P, Karaguzel A, Wollnik B：CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 43：23-26, 2011

23）Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, Kanno J, Niihori T, Ono M, Ishii N, Owada Y, Fujimura M, Mashimo Y, Suzuki Y, Hata A, Tsuchiya S, Tominaga T, Matsubara Y, Kure S：A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 56：34-40, 2011

24）Kang HS, Kim JH, Phi JH, Kim YY, Kim JE, Wang KC, Cho BK, Kim SK：Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry 81：673-678, 2010

25）Karasawa J, Kikuchi H, Furuse S, Kawamura J, Sakaki T：Treatment of moyamoya disease with STA-MCA anastomosis. J Neurosurg 49：679-688, 1978

26）小泉昭夫：より合理的なフィールド遺伝疫学をめざして．日本衛生学雑誌65：37-47, 2010

27）小泉昭夫：家族性モヤモヤ病の遺伝解析．ウイルス動脈輪閉塞症の診断・治療に関する研究　平成21年度研究報告書（主任研究員　橋本信夫），pp25-26，2010年5月

28）Kudo T：Spontaneous occlusion of the circle of Willis. A disease apparently confined to Japanese. Neurology 18：485-496, 1968

29）Kuroda S, Houkin K：Moyamoya disease：current concepts and future perspectives. Lancet Neurol 7：1056-1066, 2008

30）Lasater EA, Li F, Bessler WK, Estes ML, Vemula S, Hingtgen CM, Dinauer MC, Kapur R, Conway SJ, Ingram DA Jr：Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. J Clin Invest 120：859-870, 2010

31）Lim ES, Emerman M：HIV：Going for the watchman. Nature 474：587-588, 2011

32）Liu W, Hashikata H, Inoue K, Matsuura N, Mineharu Y, Kobayashi H, Kikuta KI, Takagi Y, Hitomi T, Krischek B, Zou LP, Fang F, Herzig R, Kim JE, Kang HS, Oh CW, Tregouet DA, Hashimoto N, Koizumi A：A rare Asian founder polymorphism of Raptor may explain the high prevalence of Moyamoya disease among East Asians and its low prevalence among Caucasians. Environ Health Prev Med 15：94-104, 2010

33）Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta K, Takagi Y, Harada KH, Fujiyama A, Herzig R, Krischek B, Zou L, Kim JE, Kitakaze M, Miyamoto S, Nagata K, Hashimoto N, Koizumi A：Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 6：e22542, 2011

34）Lücke T, Clewing JM, Boerkoel CF, Hartmann H, Das AM, Knauth M, Becker H, Donnerstag F：Cerebellar atrophy in Schimke-immuno-osseous dysplasia. Am J Med Genet A 143A：2040-2045, 2007

35）Merkel KH, Ginsberg PL, Parker JC Jr, Post MJ：Cerebrovascular disease in sickle cell anemia：a clinical, pathological and radiological correlation. Stroke 9：45-52, 1978

36）Minami Y, Oishi I, Endo M, Nishita M：Ror-family receptor tyrosine kinases in noncanonical Wnt signaling：their implications in developmental morphogenesis and human diseases. Dev Dyn 239：1-15, 2010

37）Mineharu Y, Liu W, Inoue K, Matsuura N, Inoue S, Takenaka K, Ikeda H, Houkin K, Takagi Y, Kikuta K, Nozaki K, Hashimoto N, Koizumi A：Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology 70：2357-2363, 2008

38）Miskinyte S, Butler MG, Herve D, Sarret C, Nicolino M, Petralia JD, Bergametti F, Arnould M, Pham VN, Gore AV, Spengos K, Gazal S, Woimant F, Steinberg GK, Weinstein BM, Tournier-Lasserve E：Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am J Hum Genet 88：718-728, 2011

39）Okazaki K, Kakita A, Tanaka H, Kimura K, Minagawa M, Morita T, Takahashi H：Widespread ischemic brain lesions caused by vasculopathy associated with neurofibromatosis type 1. Neuropathology 30：627-633, 2010

40）Park HW, Oh D, Kim N, Cho HY, Moon KC, Chae JH, Ahn HS, Choi Y, Cheong HI：Congenital thrombotic thrombocytopenic purpura associated with unilateral moyamoya disease. Pediatr Nephrol 23：1555-1558, 2008

41）Qaiser R, Scott RM, Smith ER：Identification of an association between Robinow syndrome and moyamoya. Pediatr Neurosurg 45：69-72, 2009

42）Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, Crow YJ：Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis. Dev Med Child Neurol 52：725-732, 2010

43）Rasmussen SA, Yang Q, Friedman JM：Mortality in neurofibromatosis 1：an analysis using U. S. death certificates. Am J Hum Genet 68：1110-1118, 2001

44）Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dorfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voss E, Wilson L, Hennekam R, de Zegher F, Dorr HG, Reis A：Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 319：816-819, 2008

45）Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ：Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 41：829-832, 2009

46）Roder C, Peters V, Kasuya H, Nishizawa T, Wakita S, Berg D, Schulte C, Khan N, Tatagiba M, Krischek B：Analysis of ACTA2 in European Moyamoya disease patients. Eur J Paediatr Neurol 15：117-122, 2011

47）Rosser TL, Vezina G, Packer RJ：Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Neurology 64：553-555, 2005

48）Saha K, Jaenisch R：Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell 5：584-595, 2009

49）Sakurai K, Horiuchi Y, Ikeda H, Ikezaki K, Yoshimoto T, Fukui M, Arinami T：A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 49：278-281, 2004

50）Salyer WR, Salyer DC：The vascular lesions of neurofibromatosis. Angiology 25：510-519, 1974

51）Shimojima K, Yamamoto T：ACTA2 is not a major disease-causing gene for moyamoya disease. J Hum Genet 54：687-688, 2009

52）Shoji Y, Koizumi A, Kayo T, Ohata T, Takahashi T, Harada K, Takada G：Evidence for linkage of human primary systemic carnitine deficiency with D5S436：a novel gene locus on chromosome 5q. Am J Hum Genet 63：101-108, 1998

53）Suzuki J, Takaku A：Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20：288-299, 1969

54）Takebayashi S, Matsuo K, Kaneko M：Ultrastructural studies of cerebral arteries and collateral vessels in moyamoya disease. Stroke 15：728-732, 1984

55）竹内一夫，清水健太郎：両側内頚動脈形成不全症．No To Shinkei 9：37-43, 1957

56）Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD：Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29：465-468, 2001

57）Terada T, Yokote H, Tsuura M, Nakai K, Ohshima A, Itakura T：Marfan syndrome associated with moyamoya phenomenon and aortic dissection. Acta Neurochir (Wien) 141：663-665, 1999

58）Thiele H, du Moulin M, Barczyk K, George C, Schwindt W, Nurnberg G, Frosch M, Kurlemann G, Roth J, Nurnberg P, Rutsch F：Cerebral arterial stenoses and stroke：novel features of Aicardi-Goutières syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression. Hum Mutat 31：E1836-1850, 2010

59）Westerman MP, Green D, Gilman-Sachs A, Beaman K, Freels S, Boggio L, Allen S, Zuckerman L, Schlegel R, Williamson P：Antiphospholipid antibodies, proteins C and S, and coagulation changes in sickle cell disease. J Lab Clin Med 134：352-362, 1999

60）Xin B, Jones S, Puffenberger EG, Hinze C, Bright A, Tan H, Zhou A, Wu G, Vargus-Adams J, Agamanolis D, Wang H：Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke. Proc Natl Acad Sci U S A 108：5372-5377, 2011

61）Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H, Inoue T, Ikezaki K, Matsushima T, Fukui M：Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 31：930-935, 2000