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Autosomal dominant moyamoya disease maps to chromosome 17q25.3

From the Departments of Health and Environmental Sciences (Y.M., W.L., K.I., N.M., S.I., A.K.) and Neurosurgery (Y.M., Y.T., K.K., K.N., N.H.), Kyoto University Graduate School of Medicine; Takayama Red Cross Hospital (K.T.); Department of Neurosurgery, Ohara Medical Center (H.I.), Fukushima; and Department of Neurological Surgery, Sapporo Medical University Graduate School of Medicine (K.H.), Sapporo, Japan.

Address correspondence and reprint requests to Dr. Akio Koizumi, Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan koizumi{at}pbh.med.kyoto-u.ac.jp

Background: Moyamoya disease (MMD) is an idiopathic steno-occlusive cerebrovascular disease that represents an important cause of stroke. However, etiology of the disease has remained largely unknown.

Methods: We previously showed that the inheritance pattern of MMD is autosomal dominant with incomplete penetrance. Here, we report the genome-wide parametric linkage analysis for MMD in 15 extended Japanese families. We conducted linkage analyses under two diagnostic classifications: narrow and broad. Affected member-only analysis was applied due to incomplete and age-dependent penetrance of the disease.

Results: Under both classifications, significant evidence of linkage was only observed on chromosome 17q25.3, with maximum multipoint logarithm of odds (lod) scores of 6.57 (under the narrow classification) and 8.07 (under the broad classification) at D17S704. Haplotype analysis revealed segregation of a disease haplotype in all families but one, and informative crossovers enabled mapping of the MMD locus to a 3.5-Mb region between D17S1806 and the telomere of 17q, encompassing 94 annotated genes.

Conclusions: Our data suggest that there is a major gene locus for autosomal dominant moyamoya disease on chromosome 17q25.3.

Abbreviations: ACAs = anterior cerebral arteries; HLOD = heterogeneity-adjusted logarithm of odds; ICAs = internal carotid arteries; MCAs = middle cerebral arteries; MMD = moyamoya disease; MRA = MR angiography; NF1 = neurofibromatosis type 1; NPL = nonparametric linkage; RCMJ = Research Committee on the Spontaneous Occlusion of the Circle of Willis of the Ministry of Health and Welfare, Japan; RFLP = restriction fragment length polymorphism; SNP = single nucleotide polymorphism.

Supplemental data at www.neurology.org

Editorial, page 2353

e-Pub ahead of print on May 7, 2008, at www.neurology.org.

*Y.M. and W.L. contributed equally to this work.

Mainly supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan to A.K. (Tokutei Kenkyu: 15012231, 16012232, 17019034, and 18018022) and grants from the Japan Society for the Promotion of Science to A.K. (Kiban Kenkyu A: 14207016 and S: 17109007). Partly supported by a grant from the Research Committee on Moyamoya Disease of the Ministry of Health and Welfare of Japan to N.H. (H17-Nanchi-Ippan-018). Y.M. is a member of Research Fellows of the Japan Society for the Promotion of Science.

Disclosure: The authors report no disclosures.

Received June 8, 2007. Accepted in final form September 12, 2007.

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				J. F. Meschia and O. A. Ross Heterogeneity of Moyamoya disease: After a decade of linkage, is there new hope for a gene? Neurology, June 10, 2008; 70(24_Part_2): 2353 - 2354. [Full Text] [PDF]