Table Of ContentCurrent Topics in
Environmental Health and Preventive Medicine
Akio Koizumi · Kazuhiro Nagata
Kiyohiro Houkin · Teiji Tominaga
Susumu Miyamoto · Shigeo Kure
Elizabeth Tournier-Lasserve Editors
Moyamoya Disease
Explored Through
RNF213
Genetics, Molecular Pathology,
and Clinical Sciences
Current Topics in
Environmental Health and Preventive Medicine
Series editor
Takemi Otsuki
Kurashiki, Japan
Current Topics in Environmental Health and Preventive Medicine, published in
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Akio Koizumi • Kazuhiro Nagata
Kiyohiro Houkin • Teiji Tominaga
Susumu Miyamoto • Shigeo Kure
Elizabeth Tournier-Lasserve
Editors
Moyamoya Disease Explored
Through RNF213
Genetics, Molecular Pathology, and Clinical
Sciences
Editors
Akio Koizumi Kazuhiro Nagata
Department of Health and Environmental Faculty of Life Sciences
Sciences Kyoto Sangyo University
Kyoto University Graduate School Kyoto, Japan
of Medicine
Kyoto, Japan Teiji Tominaga
Department of Neurosurgery
Kiyohiro Houkin Tohoku University School of Medicine
Department of Neurosurgery Sendai, Japan
Hokkaido University Graduate School
of Medicine Shigeo Kure
Sapporo, Japan Department of Pediatrics
Tohoku University School of Medicine
Susumu Miyamoto Sendai, Japan
Department of Neurosurgery
Kyoto University Graduate School of
Medicine
Kyoto, Japan
Elizabeth Tournier-Lasserve
CHU Paris‐GH St‐Louis Lariboisière
F‐Widal
Hôpital Lariboisière
Paris, France
ISSN 2364-8333 ISSN 2364-8341 (electronic)
Current Topics in Environmental Health and Preventive Medicine
ISBN 978-981-10-2710-9 ISBN 978-981-10-2711-6 (eBook)
DOI 10.1007/978-981-10-2711-6
Library of Congress Control Number: 2017933283
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Preface
More than 60 years have passed since the first case of moyamoya disease was
reported in 1955 by Japanese neurosurgeons. In the 1970s, this unique cerebrovas-
cular occlusive disease was named moyamoya disease, and its distinctive-sounding
name, together with the concomitant development of surgical treatments for moy-
amoya by Japanese surgeons, facilitated its international recognition. Further recog-
nition for moyamoya was earned after the late 1980s by Japanese neurosurgeons
through clinical epidemiological studies that suggested the involvement of genetic
factors in the development of moyamoya and the demonstration that moyamoya was
one of the major causes of stroke in the younger population. All these breakthroughs
were made by pioneer neurosurgeon groups.
At the turn of the twenty-first century, I joined a research group on moyamoya
disease as an expert of social medicine. The group was supported by the Ministry
Health and Labor of Japan and organized by Dr. Nobuo Hashimoto, professor emer-
itus of Kyoto University and one of the most prominent neurosurgeons in Japan. He
expected me as a social medicine researcher to expand the investigations on the
genetic factor(s) involved with moyamoya in collaboration with neurosurgeons.
Fortunately, in 2010 we were able to identify RNF213 R4810K (mysterin) as a
genetic factor for moyamoya disease. (Please see Chapter 1 for the official report by
this group.) However, elucidation of this genetic factor unveiled unexpected com-
plexities: given that the carrier prevalence of RNF213 R4810K is 0.8–2.0% in the
general population in East Asian countries, there is a large gap between the preva-
lence of moyamoya patients (roughly 1/10000 population) and carriers (1/50 in the
general population). This discrepancy required a rational explanation and led us to
postulate that there were additional factors, i.e., non-genetic factors, such as envi-
ronmental factors or infection, for the development of moyamoya disease.
Such a gap also strongly implies that prevention of moyamoya disease can be
best achieved by a high-risk strategy focusing on carriers. On the other hand, it
raises additional unresolved questions: what is the health risk of R4810K for carri-
ers, what is the function of RNF213, how does R4810K impair RNF213 functions,
and how does it lead to moyamoya disease in concert with non-genetic factors?
v
vi Preface
Addressing such unresolved questions is not only interesting, but also critical for
developing nonsurgical therapeutic approaches and disease-prevention strategies.
Those unsolved mysteries for RNF213 need further expansion on the horizon of
moyamoya disease with the combined efforts of molecular biologists and
biochemists.
The aim of the present book is to provide the most up-to-date information on the
role of RNF213 in moyamoya disease, not only for neurosurgeons, but also for pub-
lic health researchers and basic biological scientists. Special emphasis, therefore,
has been placed on a more comprehensive approach towards the clinical aspects,
genetic epidemiology, and biochemical and physiological functions of RNF213.
Contributors are well-known frontline clinical, social medicine, and molecular biol-
ogy researchers of moyamoya disease and RNF213 in different disciplines beyond
neurosurgery.
Current topics in our journal, i.e., Environmental Health and Preventive Medicine,
published in partnership with the Japanese Society of Hygiene, aim to deliver
cutting- edge information as explored by frontline experts from the around the globe
in a diverse area of expertise, focusing on prevention of diseases and environmental
health related to health risks. The book series is a valuable resource to researchers,
clinicians, and administrators who are seeking comprehensive information on envi-
ronmental health and health promotion. Therefore, I am very proud of this book, not
only as a researcher in social medicine, but also as the president of the Japanese
Society of Hygiene, because I am certain that our society can contribute to the pre-
vention of moyamoya disease and clearly demonstrate a pivotal role of social medi-
cine in modern health issues. Finally, all the contributors hope that this book
stimulates research on vascular diseases through the study of RNF213 and paves the
way to novel innovations for the prevention, treatment, and management of cerebro-
vascular diseases.
On the behalf of all the contributors and editors.
Kyoto, Japan Akio Koizumi
Contents
Part I Prologue
1 A Prologue to Moyamoya Disease and RNF213 ................................... 3
Akio Koizumi and Shohab Youssefian
2 Concept of Moyamoya Disease .............................................................. 13
Haruto Uchino, Ken Kazumata, and Kiyohiro Houkin
Part II Genetic Epidemiology
3 Molecular Epidemiology in East Asian Countries and
in the World ............................................................................................. 25
Wanyang Liu
Part III Biochemistry, Function and Molecular Pathology
4 Molecular Biology of Mysterin/RNF213 ............................................... 45
Daisuke Morito and Kazuhiro Nagata
5 Physiological Role of Mysterin/RNF213 in Zebrafish ......................... 59
Daisuke Morito and Kazuhiro Nagata
6 Pathological Investigation on RNF213: Animal Models
Knockout and Transgenic Mice in Diabetes
and Signal Transduction ......................................................................... 69
Hatasu Kobayashi
7 Pathological Investigation on RNF213: Animal Models
of Rnf213-Knockout and Knock-in Mice .............................................. 79
Miki Fujimura, Shigeo Kure, and Teiji Tominaga
8 RNF213 and Circulating Factors in Patients
with Moyamoya Disease ......................................................................... 91
Oh Young Bang
vii
viii Contents
9 Genetics of Moyamoya Beyond RNF213: Monogenic
Moyamoya Syndromes ........................................................................... 103
S. Guey, M. Kraemer, L. Grangeon, F. Riant,
M. Kossorotoff, D. Hervé, and E. Tournier-Lasserve
Part IV Clinical Management
10 Natural History and Long-Term Clinical Outcome
After Conservative and Surgical Management .................................... 121
Won-Sang Cho and Jeong Eun Kim
11 Significance of RNF213 in Clinical Management in Japan ................. 137
Yohei Mineharu, Yasushi Takagi, and Susumu Miyamoto
12 Significance of RNF213 in Clinical Management in China................. 151
Zheng-Shan Zhang and Lian Duan
13 The Different Forms of Moyamoya Disease
and Their Clinical Management ............................................................ 161
Niklas von Spreckelsen and Boris Krischek
14 Vascular Diseases Attributable to RNF213 Other
Than Moyamoya Disease ........................................................................ 169
Satoru Miyawaki, Hideaki Imai, and Nobuhito Saito
Part V Epilogue
15 Future Clinical Perspectives on RNF213 in Moyamoya Disease ........ 179
Shigeo Kure
Part I
Prologue
