Yamauchi et al. performing the linkage analysis focusing on chromosome 17 because the characteristic lesions of moyamoya disease are occasionally seen in neurofibromatosis type 1 and its causative gene NF1 is located on 17q11.2 [13] . A total of 24 families with moyamoya disease with multiple affected family members were analyzed with 22 microsatellite markers on chromosome 17. The result indicates that the MLS was 3.1 at the marker D17S939, and that the disease locus was encompassed within the 9-cM region between D17S785 and D17S836 on chromosome 17q25. The same group selected nine candidate genes, DNA2, AANAT, PSP, HCNGP, HN1, SGSH, SYNGR2, EVPL , and TIMP2, in the 9-cM region for mutational analysis by exon sequencing method [14] . No causative mutation was identified in the nine genes. Recently, Kang et al. performed the mutational and association analyzes of TIM2 that encodes tissue inhibitor of metalloproteinase type 2 [15] . Although they found no causative mutations in the protein-coding regions, a significantly higher frequency of a heterozygous genotype was found in the TIMP2 promoter region at position 418 in familial moyamoya disease, compared with nonfamilial moyamoya disease or control group. Vascular SMCs produce matrix metalloproteinase type 2, which plays a role in invasion and prolifera- tion of SMCs [16] . Dysregulation of TIMP2 may, therefore, lead to abnormal proliferation and intimal thickening.
Chromosome 17q25.3
Mineharu et al. reported the genome-wide parametric linkage analysis for moyamoya disease in 15 extended Japanese families by using 382 polymorphic markers [17] . They collected three-generation pedigrees and applied an affected member-only analysis after MRI and MR angiography examinations. They use two diagnostic criteria, narrow and broad. Only patients with definite moyamoya disease was assigned under narrow criteria while patients with faint steno-occlusive lesions around the terminals of the internal carotid arteries were classified as affected under broad criteria. Significant evidence of linkage was observed only on chromosome 17q25.3 with maximum multipoint LOD score of 6.57 using narrow diagnostic criteria and 8.07 using broad criteria. The moyamoya disease locus has been finally mapped
49 Genetic Linkage Study
to a 3.5 Mb region between D17S1806 to the telomere, which is close to the previously- reported moyamoya locus with 9-cM, but not overlapping [13] . The authors discussed that steno-occlusive changes of the middle cerebral artery and unilateral moyamoya disease can be considered to be in the spectrum of moyamoya disease since high linkage scores was observed under both the narrow and broad diagnostic criteria. They selected four candidate genes in the responsible region based on their gene functions, TIMP2, BAIAP2, RAC3 , and RAB40B. A promoter polymorphism of TIMP2 reported by the Korean group [15] was not polymorphic in the families. BAIAP2 interacts with brain-specific angiogenesis inhibitor-1, which is an inhibitor of basic fibroblast growth factor (bFGF)-induced angiogenesis [18] . RAC3 and RAB40B are members of the ras oncogene family and important regulators of cell growth and cytoskeletal recognition. The authors performed the mutational analysis, but they found no causative mutation in the four candidate genes.
Conclusions
Recent linkage analysis has provided compelling evidence that the pathogenic gene of moyamoya disease would be identified on chromosome 17q25.3. A complete genetic characterization of the linked region, including comprehensive sequencing of each gene and copy number analysis, is imperative to identify the moyamoya disease gene [19] . Identification of the moyamoya disease gene would permit presymptomatic screening for high-risk individuals.
References
1. Ikeda H, Sasaki T, Yoshimoto T et al (1999) Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 64:533–537
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3. Collod G, Babron MC, Jondeau G et al (1994) A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet 8:264–268
4. Mizuguchi T, Collod-Beroud G, Akiyama T et al (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36:855–860
5. Yamamoto T, Akasaka Y, Ohtani K et al (2005) Molecular screening for moyamoya disease by use of expressed sequence tag on chromosome 3p. No To Hattatsu 37:20–25
6. Aoyagi M, Ogami K, Matsushima Y et al (1995) Human leukocyte antigen in patients with moyamoya disease. Stroke 26:415–417
7. Inoue TK, Ikezaki K, Sasazuki T et al (1997) DNA typing of HLA in the patients with moyamoya disease. Jpn J Hum Genet 42:507–515
8. Inoue TK, Ikezaki K, Sasazuki T et al (2000) Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 15:179–182
9. Han H, Pyo CW, Yoo DS et al (2003) Associations of moyamoya patients with HLA class I and class II alleles in the Korean population. J Korean Med Sci 18:876–880
10. Sakurai K, Horiuchi Y, Ikeda H et al (2004) A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 49:278–281
11. Yamamoto M, Aoyagi M, Fukai N et al (1998) Differences in cellular responses to mitogens in arterial smooth muscle cells derived from patients with moyamoya disease. Stroke 29:1188–1193
12. Hojo M, Hoshimaru M, Miyamoto S et al (1998) Role of transforming growth factor-beta1 in the pathogenesis of moyamoya disease. J Neurosurg 89:623–629
13. Yamauchi T, Tada M, Houkin K et al (2000) Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 31:930–935
50 S. Kure 14. Nanba R, Tada M, Kuroda S (2005) Sequence analysis and bioinformatics analysis of chromosome
17q25 in familial moyamoya disease. Childs Nerv Syst 21:62–68
15. Kang HS, Kim SK, Cho BK et al (2006) Single nucleotide polymorphisms of tissue inhibitor of metal- loproteinase genes in familial moyamoya disease. Neurosurgery 58:1074–1080; discussion-80 16. Johnson C, Galis ZS (2004) Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle
cell migration and cell-mediated collagen organization. Arterioscler Thromb Vasc Biol 24:54–60 17. Mineharu Y, Liu W, Inoue K et al (2008) Autosomal dominant moyamoya disease maps to chromosome
17q25.3. Neurology 70:2357–2363
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51
Introduction
Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that can contribute to disease susceptibility. Although more than 12 million SNPs have been identified, most of them are not associated with disease susceptibility [1] . Moyamoya disease (MMD) is more common in Asian populations; however, we do not know the reason for this.
Genetic studies using SNPs may provide the answer. For example, an SNP in the promoter region of the tissue inhibitor of metalloproteinase 2 gene ( TIMP2 ) is related to the occurrence of familial MMD [2] . High-throughput SNP genotyping may be fruitful in this field of research.