A new horizon of moyamoya disease and associated health risks explored through RNF213
Environ Health Prev Med
A new horizon of moyamoya disease and associated health risks explored through RNF213
Akio Koizumi 0 1 2 3 4
Hatasu Kobayashi 0 1 2 3 4
Toshiaki Hitomi 0 1 2 3 4
Kouji H. Harada 0 1 2 3 4
Toshiyuki Habu 0 1 2 3 4
Shohab Youssefian 0 1 2 3 4
0 Department of Preventive Medicine, St. Marianna University School of Medicine , Sugao, Miyamae-ku, Kawasaki 216-8511 , Japan
1 Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University , Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501 , Japan
2 & Akio Koizumi
3 Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University , Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501 , Japan
4 Laboratory of Nutritional Sciences, Department of Food Science and Nutrition, Mukogawa Women's University , Ikebirakicho 4-46, Nishinomiya 663-8558 , Japan
The cerebrovascular disorder moyamoya disease (MMD) was first described in 1957 in Japan, and is typically considered to be an Asian-specific disease. However, it is globally recognized as one of the major causes of childhood stroke. Although several monogenic diseases are known to be complicated by Moyamoya angiopathy, the ring finger protein 213 gene (RNF213) was identified as a susceptibility gene for MMD. RNF213 is unusual, because (1) it induces MMD with no other recognizable phenotypes, (2) the RNF213 p.R4810K variant is an Asian founder mutation common to Japanese, Korean and Chinese with carrier rates of 0.5-2 % of the general population but a low penetrance, and (3) it encodes a relatively largest proteins with a dual AAA? ATPase and E3 Ligase activities. In this review, we focus on the genetics and genetic epidemiology of RNF213, the pathology of RNF213 R4810K, and the molecular functions of RNF213, and also address the public health contributions to current unresolved issues of MMD. We also emphasize the importance of a more updated definition for MMD, of qualified cohort studies based on genetic epidemiology and an awareness of the ethical issues associated with genetic testing of carriers.
Moyamoya disease; RNF213 R4810K; Asian founder mutation; Angiogenesis; Hypoxia
Moyamoya disease (MMD) is a steno-occlusive disease of
the cerebral arteries, involving smooth muscle cell
proliferation with intima hyperplasia causing arterial stenosis and
occlusion around the circle of Willis [
] (Fig. 1). This, in
turn, stimulates the compensatory development of collateral
vessels, which have a ‘‘Puff of Smoke’’ (Moyamoya in
Japanese) appearance in cerebral angiography .
MMD is currently recognized as one of the major causes
of stroke in children worldwide [
]. Natural disease
progression leads to cerebral hemorrhage or cerebral
infarction, so early diagnosis and intervention before the
establishment of a neurological deficit are essential for
improved social adaptation of pediatric patients .
Nationwide epidemiological surveys are available in Japan
and Korea because of the existence of registration
programs. The prevalence and annual incidence of MMD in
Japan were reported to be 10.5 and 0.94 per 100,000,
respectively, while in Korea these figures were 18.1 and 4.3
per 100,000, respectively, in 2013 [
]. An estimated
100–15 % of MMD patients have family histories [
Several monogenic genetic diseases are known to lead to
the development of MMD as a complication, referred to as
Discordant moyamoya phenotype in familial cases with moyamoya disease
moyamoya syndrome (Table 1). In such diseases, MMD is
not the major phenotypic presentation, but it appears to
develop in some but not all cases with low penetrance. A
comprehensive review of the genetics of MMD associated
with monogenic gene diseases has recently been published
]. Impaired biological processes (signal transduction,
chromatin remodeling, DNA repair, inflammation,
hemostasis, and vascular smooth muscle cell coagulation),
attributable to mutations of associated genes, have given
insights into the mechanisms by which the mutations
elevate the risk of MMD. However, no consolidated
pathological process for MMD development has yet been
The ring finger protein 213 gene (RNF213), (mysterin),
was recently identified as a susceptibility gene for MMD.
RNF213 is unusual among susceptibility genes, because it
induces MMD with no other phenotypic traits. The
RNF213 variant p.R4810K (c.14429G [ A, rs112735431,
ss179362673, R4810K hereafter) was first reported by the
Kyoto group with a high level of association (odds ratio
63.9 95 %, confidence interval 33.9–120.4) [
] and shown
to be associated with MMD at large scales [
R4859K  and R4810K [
] correspond to
rs112735431, but while R4859K is based on the
computerpredicted open-reading frame in the database [
cerebral infarction. Her niece also developed MMD (II-3). Subjects
I3, II-1, II-2, and II-3 all shared the WT/R4810K genotype. We
assumed the carrier status for I-2, I-3, and II-2 in our linkage analysis.
Due to the rarity of the disease gene, we assumed that I-2 is a carrier
of the MMD-associated gene. This pedigree is simplified from the
original pedigree 14 [
is based on the experimental open-reading frame, which
was proven by cDNA cloning [
]. Thus, in this review, we
use R4810K. Liu et al. [
] later reported that RNF213
R4810K is a founder variant in East Asian (Japanese,
Korean, and Chinese) patients. Indeed, in Japan and Korea,
the majority (*80 %) of MMD patients carry at least one
allele of RNF213 R4810K [
]. A much larger
proportion of carriers with RNF213 R4810K is known to
develop MMD than that of wild-type (WT) subjects, even
though most carriers are unaffected by the disease. This
can be explained by the effect of environmental or other
genetic factors that elevate the risk of MMD in concert
with genetic predisposition. Because the total number of
these carriers is estimated to be 15 million in Asian
countries, the social impact as a single health issue is
extremely significant .
RNF213 is composed of 5207 amino acids and has an
estimated molecular size of 591 kDa. Its large size initially
hampered full-length cDNA cloning, which was first
achieved in 2011 [
]. Since then, the biochemical and
functional characterization of RNF213 has progressed [
], especially through the use of mouse gene ablation
20, 22, 23
], transgenic mouse models , and
an induced pluripotent stem cell (iPSC) model established
from patients with MMD [
Cell cycle, DNA repair
Vascular smooth muscle cell
Notch signal pathway
Wnt signal pathway
Excessive Type I interferon
This review addresses recent research progress in MMD
with regard to effective prevention and intervention
programs, enabling public health researchers to identify clear
public health goals. In particular, it focuses on RNF213 in
terms of the public health aspect of MMD.
Multiple genetic loci on 17q25.3 in Japanese patients with familial MMD
MMD has two phenotypic characteristics. The first is
apparent from the pathological investigation of cerebral
arteries, and involves smooth muscle cell proliferation and
neointimal formation with thrombi at the occlusive lesion
]. This characteristic forms the basis for the
alternative name of MMD; sontaneous occlusion of the circle of
]. Confirmation of this characteristic requires
tissue samples for pathological examination, and so it is not
practical. The second characteristic is the appearance of
moyamoya vessels [
] in angiography, which has been
widely used as the diagnostic criterion because of the ease
of access in a clinical setting [
]. Current diagnostic
criteria of MMD require bilateral stenosis and moyamoya
vessels to be observed, while cases with stenosis around the
circle of Willis, but the absence of moyamoya vessels, or
unilateral stenosis are excluded. However, MMD disease
progression starts with stenotic lesions, then leads to
unilateral MMD, and culminates in bilateral stenosis with the
Type I neurofibromatosis
Moyamoya and achalasia
Thoracic aortic aneurysm
Sickel cell disease
development of collateral vessels [
]. Therefore, these
criteria only cover advanced stage MMD, and exclude
cases at an earlier disease stage.
To date, five loci have been reported in Japanese MMD
cases: 3p24–p26 [
], 6q25 [
], 8q23 [
], and 17q25/
]. Linkage analyses were applied to all loci,
with the exception of 6q25, in which the association of
HLA with MMD was conducted . Loci variation is
noteworthy because it argues against the epidemiological
observation of a single major locus (17q25.3), and because
it is linked with the default application of current
diagnostic criteria. As the status of MMD is judged solely by
the clinical diagnostic criteria, cases with stenosis only or
unilateral MMD are eliminated and treated as
‘‘unaffected’’, thereby rejecting the autosomal dominant mode of
]. Given that more than 80 % of
Japanese patients with MMD are carriers of RNF213 R4810K,
many researchers are skeptical about such versatility of
genetic loci (3p24–p26 and 8q23) in Japanese pedigrees. In
earlier studies, the dogmatic application of clinical
diagnosis elicited the genetic problem known as ‘‘skipping of
generations’’. For example, when a grandparent and
grandchild are affected with MMD but the grandparent’s
daughter, i.e., the mother, only has stenosis, the ‘‘skipping
generation phenomenon’’ occurs. Several examples can be
found in the study by Liu et al.  (Fig. 1).
To overcome these genetic irregularities, Mineharu et al.
] conducted a genome-wide linkage analysis by
introducing a ‘‘carrier state’’, which widened the clinical
spectrum and included phenotypes, such as stenosis, unilateral
cases, or the absence of abnormalities (Fig. 1). They
analyzed 15 three-generation pedigrees and obtained a single
and strong linkage signal at 17q25.3 (LOD score 8.11,
p = 3.4 9 10-6)with an autosomal dominant mode of
inheritance. The locus at 17q.25.3 has been confirmed
repeatedly by different family sets [
], and has led
to the initial identification of the susceptibility gene,
RNF213. However, confirmation is warranted for the other
loci on 3p24–p26, 8q23, and 17q25.
Genetics of RNF213 mutations
R4810K and other mutations
Our previous studies showed that in East Asia, the founder
variant RNF213 R4810K was much more frequently found
in MMD patients (Japanese, 90.1 %; Korean, 78.9 %;
Chinese, 23.1 %) than the general population (Japanese,
2.5 %; Korean, 2.7 %; Chinese, 0.9 %) [
on from these studies, several groups also identified
RNF213 R4810K in MMD patients from Taiwanese,
Indian, Bangladeshi, and Filipino populations [
14, 15, 37
RNF213 R4810K was found to be absent from control
individuals as well as Caucasian MMD cases [
which may explain their lower incidence of MMD. Indeed,
the MMD incidence in Caucasians was estimated to be
one-tenth of that in the Japanese population [
Many non-R4810K mutations in RNF213 have,
however, been identified in both Asian and Caucasian MMD
cases (Fig. 2; Table 2) [
11, 12, 14, 15, 37, 39
mutations have two characteristics: (1) they cluster at the
C-terminal portion of RNF213, and (2) they do not fall into
the category of null mutations resulting in a
loss-of-function (nonsense or frame-shift mutations). Almost all
RNF213 mutations, including R4810K (30 out of 32,
expect for A529del and A1622V), are located within exons
41–68 (NM_001256071.2), corresponding to the region
from the RING finger domain to the C-terminus of the
RNF213 protein. Additionally, all 32 mutations are
missense, in-frame deletions (A529del and K4115del), or
inframe insertions (E4950_F4951ins7). This suggests that the
mutations have a dominant negative or gain-of-function
effect. Indeed, mutations in the C-terminal portion of
RNF213 would be predicted to cause functional alterations
of the protein, which is more likely to be linked to a
dominant negative or gain-of-function than a
Interestingly, five of these non-R4810K mutations are
thought to be disease causing. D4013N in Caucasian
patients and E4950D and A5021V in Chinese patients,
originally identified by our group [
], have also been
independently reported by others [
segregation was confirmed both in European  and
] MMD pedigrees, raising the possibility that
D4013N may have a founder effect in Caucasian
populations worldwide. Furthermore, the two de novo mutations
] and S4118F [
] have been identified in
Caucasian cases. They are located in close proximity to
each other, and were detected in early onset (\1-year-old)
MMD patients, indicating that mutations in this region
might have severe deleterious effects on RNF213 function.
Gene dosage effects
Gene dosage effects of RNF213 R4810K have been
reported in a clinical genetics/epidemiological study and a
case report by Miyatake et al. [
]. Homozygous RNF213
R4810K (AA) carriers with MMD were observed, but
homozygosity was not seen in unaffected controls.
Moreover, homozygosity was also associated with an earlier age
of onset and greater disease severity compared with MMD
cases harboring heterozygous RNF213 R4810K (GA) [
In the case report study, which described sibling MMD
cases with homozygous and heterozygous RNF213
R4810K, the age of disease onset in the homozygote
(AA number) 1
Fig. 2 Variants shown are described previously [
11, 12, 14, 15, 37,
] (see details in Table 2). Variants in Asian and Caucasian patients
are shown above and below the protein, respectively. The domain
structure was based on . AA amino acid, AAA? ATPase
associated with diverse cellular activities domain, RING ring finger
sibling was earlier than that of the heterozygote sibling,
and the latter developed a milder clinical course [
authors, therefore, claimed that the dosage of RNF213
R4810K alleles was strongly associated with clinical
phenotype, even in family members sharing a similar genetic
background. However, we have observed homozygous
RNF213 R4810K carriers in an unaffected control
], and also found sibling MMD cases,
including identical twins, with the same dosage of RNF213
R4810K alleles but discordant phenotypes . Therefore,
it appears that heterogeneity of the MMD phenotype
cannot be explained solely by gene dosage effects; indeed,
environmental factors may play a critical role in phenotype
Molecular characterization of RNF213
Molecular characterization of RNF213 as an AAA1
ATPAse (ATPase associated with diverse cellular activities)
The full-length cDNA of RNF213 was first cloned by Liu
et al. [
]. It was found to code for a relatively large
protein which functions both as an AAA? ATPase and an
E3 ligase (Fig. 2).
Various cell functions are mediated by AAA ?
ATPases, including membrane fusion/transport (NSF/Sec18p),
proteolysis (ClpA), heat shock protein and protease
Hsp78), motors (dyneins), protein disaggregation/refolding
(Shp104/Hsp78/ClpB), DNA recombination/repair (RuvB,
Rad17, Rfc2-5), and mitosis/meiosis (Cdc48p, Katanin)
]. Morito et al. [
] demonstrated that RNF213 has two
AAA? modules and takes a hexamer form.
Oligomerization is initiated by ATP binding in the Walker A motif of
the first AAA? module. This oligomer complex is then
relaxed after ATP hydroxylation by the Walker B motif of
the second AAA?. The cyclicity of ATP binding and ATP
hydrolysis is required to generate a moving action for many
AAA? ATPases [
], which convert the chemical energy
of ATP to physical energy (for example dyneins), but the
role of Walker A and B motifs in maintaining ATP
cyclicity is unknown.
Several diseases are known to be caused by AAA?
ATPase dysfunction, for example, PEX1/PEX6 mutations
cause multiple organ degeneration such as Zellweger
], while mutations in Cdc48 cause
amyotrophic lateral sclerosis [
]. MMD is the only
cerebrovascular or cardiovascular disease known to be
associated with an AAA? ATPase.
As RNF213 also has E3 ligase activity [
], it may
additionally play a role in protein degradation or signaling
processes. However, the complete physiological functions
of RNF213 remain unknown as no investigations have been
made into its dual AAA? ATPase and E3 ligase activities,
and its cofactors have not yet been identified.
Interferons as natural regulators of RNF213 expression
MMD patients have been shown to have elevated levels of
several growth factors in their cerebrospinal fluid,
including basic fibroblast growth factor [
growth factor-b [
], platelet-derived growth factor [
hepatocyte growth factor [
], and an uncharacterized
4473 Da peptide [
]. Recently, two groups have
independently found that RNF213 is induced by interferons
Kobayashi et al. [
] demonstrated that IFNb and IFNc
induce RNF213 transcription in an endothelial cell
(EC)specific manner. This induction is mediated by the STAT
box in the RNF213 promoter region. Ohkubo et al. [
also found that IFNc and tumor necrosis factor-a
synergistically activate RNF213 transcription both in vitro and
in vivo. They found that the AKT and PKR pathways
contribute to the up-regulation of RNF213, although it
remains to be determined what form of cellular signaling
these are involved in. Further studies are needed to
elucidate the complete signaling pathways associated with
Lowered angiogenicity of endothelial cells (ECs) as a pathological effect of RNF213 R4810K
Kim et al. [
] reported that circulating endothelial
progenitor cells obtained from patients with MMD are
defective in angiogenic functions, as judged by the tube
formation assay. This observation was unexpected because
moyamoya vessels were thought to represent a
hyperangiogenic phenomenon. This finding stimulated the
ECs derived from MMD patient iPSCs show unique
EC-specific gene expression profiles
To obtain an MMD disease model, iPSCs were established
from fibroblasts donated from six subjects [
wildtype controls, two RNF213 R4810K heterozygotes (one
affected and the other not affected with MMD), and two
patients homozygous for RNF213 R4810K. iPSC ECs
(iPSECs) were differentiated from iPSCs, and those
derived from heterozygotes or homozygotes showed
significantly decreased angiogenic activities compared with
control iPSECs in accordance with the observation of Kim
et al. [
]. In parallel, features of lowered angiogenic
activity were recapitulated in human umbilical venous
endothelial cells (HUVECs) overexpressing RNF213
R4810K, but not in those overexpressing WT RNF213.
These authors also conducted expression array analyses in
fibroblasts and counterpart iPSECs from the same donors.
They observed differential expression profiles of mRNAs
in iPSECs derived from controls and carriers of RNF213
R4810K, but none in the fibroblasts from the same donors.
A total of 121 genes were down-regulated (Supplemental
Table 1) and 36 genes were up-regulated (Supplemental
Table 2) [
]. These expression profile differences were
considered to be functionally related to the lowered
angiogenic activities of ECs. These observations strongly
indicated that differentiation from stem cells (i.e., iPSCs)
to ECs induced a change of the gene expression profile by
Attention was focused on cell cycle-associated genes
(Supplemental Table 1, asterisks), because they were
enriched by gene ontology category analysis as
downregulated in iPSECs from RNF213 R4810K carriers. The
expression of one of these genes, the key mitotic player
Securin (PTTG1), which activates angiogenesis [
investigated in HUVECs and shown to be inhibited by
RNF213 R4810K overexpression [
]. RNA silencing of
Securin in HUVECs and wild-type iPSECs was found to
inhibit angiogenesis, indicating that RNF213 R4810K
lowers angiogenesis, at least in part, by the
down-regulation of Securin. As this work only focused on a single gene
out of the 128 identified, the biological implication of the
expression profile differences found in iPSECs requires
Tube formation, a comprehensive measure of
angiogenic activity, is affected by various factors, such as EC
proliferation rates and maturity [
]. As the overexpression
of RNF213 R4810K inhibited HUVEC proliferation,
Hitomi et al. [
] further investigated the effects of RNF213
R4810K on the cell cycle using HeLa cells, fibroblasts, and
iPSECs. They found that overexpression of RNF213
R4810K, but not WT RNF213, delayed mitosis in HeLa
cells, and that this was associated with abnormal
mobilization of the metaphase–anaphase spindle checkpoint
protein, mitotic arrest deficient 2 (MAD2). This abnormal
mobilization was also seen in patient fibroblasts.
Furthermore, both WT and mutant RNF213 could be
co-immunoprecipitated with MAD2. Finally, iPSECs from
MMD patients had higher mitotic failure rates than those
Collectively lowered angiogenic activity in vitro data
suggest that RNF213 R4810K acts on EC signal production
and proliferation/cell cycle. Deleterious cell
proliferation/cell cycles are mediated by Securin and/or MAD2,
which cross-talk with mutant, and probably WT, RNF213.
As cell cycle abnormality is a common denominator for
some monogenic diseases, such as Schimke
immuno-osseous dysplasia, MOPDII, or Seckel syndrome (Table 1),
further studies are warranted to explore this.
Lowered angiogenicity of RNF213 R4810K
as an AAA 1 ATPase
Kobayashi et al. [
] investigated the effects of RNF213
R4810K induction on angiogenic activity, as measured by
tube formation and by the migration assay. They confirmed
that treatment with IFNb, a cytokine that inhibits both
angiogenesis and arteriogenesis [
angiogenesis in iPSECs (Fig. 3). This reduced angiogenesis
could be rescued either by STAT box (Signal Transduction
and Transcription) or RNF213 depletion in HUVECs. This
led to the conclusion that the reduced anti-angiogenic
activity of IFNb is partially mediated by RNF213, which
acts as a mediator downstream of the IFNb signaling
pathway. They also confirmed that overexpression of
RNF213 R4810K, but not WT RNF213, can recapture the
reduced angiogenicity induced by IFNb, suggesting that
RNF213 R4810K overexpression mimics IFNb action.
Morito et al. [
] demonstrated that disruption of
Walker A or B motifs on the first or second
AAA ? modules decreases ATPase activity. However,
while both motifs are necessary to maintain the oligomeric
state, the Walker B motif has little impact on
oligomerization. Furthermore, Morito et al. demonstrated that
RNF213 R4810K forms a hexamer complex similar to the
WT protein. Kobayashi et al. [
] further investigated the
AAA? ATPase mechanism by overexpressing various
mutants in HUVECs: vector, RNF213 WT, RNF213
R4810K, a mutation of RNF213 Walker B motif (E2488Q)
on the first AAA? module (RNF213 WEQ), which disrupts
ATP hydrolysis activity, and RNF213 first AAA? module
deletion mutant (RNF213 DAAA). They found that
RNF213 R4810K and RNF213 WEQ, but neither RNF213
WT nor RNF213 DAAA, inhibited angiogenesis compared
with the vector alone. They further showed that the ATPase
activity was decreased in HUVECs transfected with
RNF213 R4810K, RNF213 WEQ, and RNF213 DAAA.
These results indicate that RNF213 R4810K is a molecular
mimic of RNF213 WEQ. This also suggested that the
Walker B motif in the first AAA? module is functionally
important in manifesting the function of ECs. A possible
explanation for this is that disruption of the RNF213 first B
motif disrupts ATP hydrolysis cyclicity, thereby inhibiting
angiogenesis. As RNF213 R4810K is considered to have a
similar mode of action to RNF213 WEQ, we speculate that
it impairs the ATP hydrolysis cycle in the same way as the
Walker B mutation.
RNF213 R4810K showed a reduced angiogenesis response to hypoxia in vivo
Kobayashi et al. [
] also focused their attention on the
effects of RNF213 R4810K on angiogenesis after hypoxia
exposure in vivo. They developed transgenic mouse (Tg)
strains overexpressing RNF213 R4757K (the mouse
homolog of human R4810K) in ECs or vascular smooth
muscle cells (SMCs).
Hypoxia is known to induce angiogenesis in the
]. Mice were exposed to hypoxia (8 % O2) for
2 weeks from 3 weeks of age. Angiogenesis was found to
be specifically reduced in Tg-ECs overexpressing RNF213
R4757K compared with other strains, i.e., Tg-SMCs
overexpressing RNF213 R4757K or Tg WT RNF213
overexpressing RNF213 wild type specifically in ECs or
RNF213 knock-out (KO) or WT mice (Fig. 4). The authors
could recapture the lowered angiogenicity of Tg ECs
in vivo, but magnetic resonance imaging failed to identify
stenosis in the cerebral arteries or infarction.
Fig. 3 Inhibition of angiogenesis by INFb and lowered angiogenic
activity of iPSECs established from controls and patients. iPSCs were
established from controls and patients with MMD. Mature iPSECs
were developed from iPSCs as reported by Hitomi et al. [
a Treatment with INFb induced mRNA of RNF213 significantly.
b Tube formation was lowered in patients. Treatment with INFb
inhibited tube formation for iPSEECs from patients. Cited from
Kobayashi et al. [
As lowered angiogenesis induced by RNF213 R4810K
(R4757K in the mouse) observed in the in vitro ECs
(HUVEC or iPSECs) could be successfully recaptured in
the Tg mouse model overexpressing RNF213 R4757K, this
suggested that ECs of RNF213 R4810K carriers may have
a lowered angiogenicity and be particularly susceptible to
Other relevant studies
RNF213 KO mice were established by Kobayashi et al.
], but did not induce abnormalities in the cardiovascular
system. The effects of RNF213 ablation of diabetic
progression were studied in the Akita mouse [
develops diabetes through an unfolded protein response of
insulin 2. The authors tested whether RNF213 ablation
(KO) influenced the development of diabetes and
intracranial arteries around the circle of Willis. Although
no stenosis was detected in the cerebral arteries of the
RNF213 KO mouse, significant alleviation of endoplasmic
reticulum (ER) stress was observed in pancreatic beta cells.
Because ER stress enhances protein degradation and
consequently depletes insulin levels in the Akita mouse, the
authors speculated that RNF213 is involved in protein
degradation as an E3 ligase in the proteasome.
Sonobe et al. [
] investigated the effects of RNF213
KO on vascular anatomy. They investigated cranial arteries
using high-resolution magnetic resonance angiography, but
found no abnormalities. They also investigated the effects
on vascular remodeling after ligation of the carotid artery,
but could not replicate the stenotic region, a hallmark of
MMD. Conversely, Ito et al. [
] recently reported the
recovery of blood flow after hind limb ischemia by femoral
artery ligation in RNF213 KO mice. Recoveries were
enhanced in RNF213 KO mice compared with WT
counterparts. Although RNF213 KO animal models have
yielded conflicting results in the cerebrum and hind limbs,
Fujimura et al. [
] speculated that RNF213 influences
vascular remodeling in chronic ischemia.
Inconsistencies necessitate additional experiments
Liu et al. [
] found that the inhibition of RNF213
expression in zebrafish induces abnormal arteriogenesis,
Fig. 4 Lowered adaptive cerebral angiogenesis after exposure to
hypoxia in transgenic mice expressing RNF213 R4757K in
endothelial cells. a Several lines of transgenic or knockout or wild-type mice
were exposed to hypoxia for 2 weeks at 8 % oxygen. Cerebral
angiogenesis was evaluated by immunostaining Glut4. b Adaptive
but this is not observed in KO mouse models [
despite the enhanced post-ischemic angiogenesis seen in
the KO mouse [
]. This finding may be physiologically
compatible with lowered angiogenesis in the cerebrum
after hypoxic exposure in EC-specific R4757K Tg mice
]; thus, the overexpression of RNF213 R4758K in ECs
inhibits angiogenesis and conversely RNF213 depletion
Further discrepancies are noted between the observed
inhibition of angiogenesis following RNF213 R4810K
] and that in HUVECs following
RNF213 depletion [
]. These differences are associated
with the controversies in the reported RNF213 R4810K
genetic mechanisms, involving loss-of-function,
], and dominant negative .
Alternatively, they could reflect species differences in innate
immunity, e.g., of zebrafish and mice [
], and further
studies are needed to resolve these discrepancies.
EC-Mut-Tg: Transgenic mice overexpressing RNF213 R4757K in ECs
EC-WT-Tg: Transgenic mice overexpressing RNF213 WT in ECs
SMC-Mut-Tg : Transgenic mice overexpressingRNF213 R4757K in SMCs
KO: RNF213 Knock-out mice
WT: wild mice
* Significantly different (p<0.05)
H: Hypoxia N: Normoxia
cerebral angiogenesis was abolished in transgenic mice
overexpressing RNF213 R4757K (Human allelic ortholog of R4810K) in ECs,
while in other mice adaptive angiogenesis was observed. Cited from
Kobayashi et al. [
Hypothetical pathological roles of RNF213 R4810K in MMD
Three major abnormalities: ECs, SMCs, and hemostasis
Several monogenic diseases have been reported to be
complicated by MMD (Table 1). As various biological
processes are involved in these diseases, including signal
transduction, chromatin remodeling/DNA repair, DNA
repair/angiogenesis, inflammation, vascular smooth muscle
cell dysfunction, and coagulopathy, the pathological
process of MMD cannot be explained in a consolidated
signaling pathway. However, the diseases can be classified
into three major abnormalities: (1) impaired functions of
ECs, (2) SMC dysfunction, and (3) hemostasis
abnormalities. For simplicity, we would like to propose an intuitive
working hypothesis based on Table 1 and recent findings
on RNF213. For analogy, we call this a three-route model
(Fig. 5), in which MMD can occur through three different
routes. These routes lead to the common outcome of SMC
In the first route, RNF213 functions as a key mediator in
ECs. Given that Type I IFN overproduction (Aicardi–
Goutieres syndrome) [
] is complicated by MMD and
RNF213 is highly activated by IFNs [
pro-inflammatory signals enhance IFN overproduction, which then
activates RNF213 transcription. It should also be noted that
pro-inflammatory signals can be induced by viral infections
or by damaged, unrepaired DNA . Amplified
pro-inflammatory signals can lead to thrombosis, as seen in
Sneddon’s syndrome [
In the second route, SMC dysfunction, which leads to
exaggerated SMC proliferation, is a major outcome.
Alphaactin-2 (ACTA2) and guanylate cyclase 1 (GUCY1A3) are
known to promote vascular SMC proliferation and induce
]. While ACTA2 mutation causes moyamoya
syndrome with thoracic aortic aneurysm and dissection by
the mode of autosomal dominant, GUCY1A3 induced
moyamoya syndrome with achalasia in the mode of
autosomal recessive. It is of particular interest that GUCY1A3
encodes the major nitric oxide receptor. In Alagille
syndrome (involving the Ras pathway), the impaired
differentiation of both ECs and SMCs occurs .
The last route is associated with hemostasis. Several
diseases in this category are known to induce hemostatic
abnormalities, including Sickle-cell disease [
of protein S and protein C [
thrombocytopenic purpura , and Noonan syndrome [
Furthermore, genes in the Ras signaling pathway [
] and Wnt
signaling pathway [
] influence platelet activation.
Activated thrombi formation results in ischemia and thereby
causing hypoxia. In addition, Ras pathways may also
trigger vascular inflammation [
] or SMC dysfunction
] in a direct way.
Hypoxia, vascular injury, or chronic inflammation generate pro-inflammatory signals: stimulators of stenosis (neointimal formation)
It has been consistently demonstrated that RNF213
R4810K lowers angiogenic activities in ECs [
21, 24, 53
but it remains unclear how this leads to stenosis
(neointimal formation). This may be answered by examining
proinflammatory signals, such as those involved in the
], vascular injury [
], and chronic
inflammation accompanied by elevated Type I IFNs [
are known to activate EC mobilization for angiogenesis,
which in turn leads to the production of adhesion
molecules, cytokines, and chemokines. These
pro-inflammatory signals stimulate SMC proliferation, migration, and
secretion of extracellular matrix, causing neointimal
]. Recently, IFN regulatory factors, activated
by IFNa/b, were reported to modulate neointimal
formation with sirtuin (SIRT)1 [
]. Given that RNF213
R4810K is a mimic of IFNb, it may amplify the effects of
IFNa/b, thereby magnifying neointimal formation by
perturbing the IRF9/SIRT1 axis. The investigation of
cytokine signaling in cells expressing RNF213 R4810K is
expected to provide answers to several of these pending
Hypothe cal three routes to vascular stenosis
Viral infec on
IFN β or IFN γ
Protein S, Protein C,
abnormal func on
prolifera on of
SMCs due to SMC
Fig. 5 Three-route model of
the hypothetical molecular
pathology of moyamoya
disease/syndrome. The model
assumes that any of three
endothelial dysfunction, smooth
muscle cell dysfunction, and
abnormal hemostasis, can lead
to exaggerated proliferation of
SMCs. Each abnormality can
result in vascular stenosis.
RNF213 R4810K is the major
detrimental factor that elicits
endothelial cell dysfunction.
Pro-inflammatory signals such
as IFNs can activate the
transcription of RNF213
Future public health contributions to MMD
Since RNF213 was identified as a susceptible gene for
MMD and as a founder mutation carried by 15 million
people from the East Asian population [
], it has emerged
as a key player in vascular disease. However, recent
progress has also resulted in some unanswered questions, such
as how can RNF213 R4810K describe the entire spectrum
of the diseases associated with MMD? What is the health
risk to RNF213 R4810K carriers? Can environmental
factors explain the observed low penetrance of one in 150
carriers developing MMD?
Although in vitro and in vivo experimental approaches
are expected to address many of these unresolved
biomedical questions, well-designed human
epidemiological studies are also essential. Given the large number of
RNF213 R4810K carriers in the general population, there is
an urgent need to evaluate their health risks. In parallel,
ethical issues should be taken into account to avoid genetic
stigmatization of these carriers.
A broader definition of MMD
The current diagnosis of MMD is based on the definition
of the angiographic appearance of moyamoya vessels.
However, RNF213 R410K genetics has unveiled
different stages of disease progression. Given that 80 % of
MMD cases are carriers of RNF213 R4810K, a definition
of MMD based on this seems broader than one based on
angiography. Another enigma is the difference between
MMD and moyamoya syndrome. Chong et al. [
recently reported a Down syndrome case with MMD,
who is a carrier of RNF213 R4810K. This indicates that
the interaction of RNF213 R4810K with other genes can
lead to the manifestation of MMD. Within this context,
the relationship between MMD syndrome and RNF213
should be examined and thereby definition of MMD
being expanded. Indeed, a broader diagnostic criterion
based on RNF213 is needed to illustrate the entire
spectrum of MMD, as well as to delineate the natural
course of carriers of RNF213 mutations in an
Health risks associated with RNF213 R4810K
Prevalence of stenotic lesions or MMD was significantly
higher (larger than 20 %) in the carriers of R4810K, if the
carrier has family history of MMD [
]. The high risk
among carriers in familial MMD shows a sharp contrast
with the low risk of carriers in general population. Thus,
carriers in the familial MMD is worthy for follow-up to
ensure the early intervention.
Recently, Koizumi et al. [
] conducted a genetic
epidemiological study with a case–control design (N = 4308)
to investigate the association of RNF213 R4810K with
blood pressure in the general Japanese population. They
found 60 carriers (1.4 %). Regression analysis adjusted for
age, sex, and body mass index based on the additive model
demonstrated significant association with systolic blood
pressure (mmHg/allele): b (Standard errors) 8.9 (2.0)
(p = 10-5). In contrast, diastolic blood pressure did not
show the association. Those data strongly indicate that
RNF213 R4810K is a risk factor of blood pressure in
freeliving carriers in general population.
Monogenic diseases stochastically associated with
MMD are often accompanied by coronary heart diseases
(CHD) (BRCC3 [
] and ACTA2 [
]). Similarly, several
case studies have reported the association between MMD
and CHD [
]. Recently, Nam et al.  found that
4.6 % of 456 MMD patients were affected with CHD.
Because these patients were young and lacked CHD risk
factors, this suggests that CHD may be accelerated by the
presence of RNF213 R4810K.
In early pathological studies [
], arterial stenosis
was found to occur systematically, not only in the
intracranial arteries but also in coronary, pulmonary, renal,
and pancreatic arteries. Therefore, RNF213 R4810K
carriers may have ischemic damage in these organs. These
findings collectively imply that stenotic regions occur in
various arteries and suggest the existence of both
cardioand cerebrovascular risks. Future large-scale genetic cohort
studies should evaluate the risk of RNF213 R4810K on
health outcomes of cardio- and cerebrovascular diseases,
such as ischemic stroke, hemorrhagic stroke, myocardial
infarction, and hypertension.
Environmental factors to explain low penetrance
The total number of registered MMD patients in 2012 was
15,177 in Japan (http://www.nanbyou.or.jp/entry/3664,
Aug 5, 2015). Assuming that 80 % of these patients are
carriers, the prevalence of MMD is 10-4. Carriers are
estimated to be 2 % of the general population, resulting in
only one out of *150 carriers developing MMD.
Therefore, another factor is needed to explain such a 1/150 low
Kaku et al. [
] reported that vascular constrictive
changes of affected arteries occur in MMD in comparison
with other steno-occlusive diseases. It is uncertain whether
such changes represent anatomical abnormalities involving
narrowing of the cavernous sinus. Given that these are rare,
they may increase the risk of MMD for RNF213 R4810K
carriers. The constrictive remodeling hypothesis can be
tested in animal models by introducing stenosis in the
carotid artery. However, to date, ligation of the carotid
artery has failed to replicate intimal hyperplasia when
applied to the RNF213 ablation mouse [
]. Further studies
are, therefore, warranted to test this hypothesis.
Inflammation is another possibility to explain such a low
penetrance. Kobayashi et al. [
] and Ohkubo et al. [
recently demonstrated that IFNs activate RNF213
transcription, so inflammation may induce MMD in association
with RNF213 R4810K.
Yamashita et al. [
] reported that thrombi formation
predominantly occurs in intracranial arteries of MMD
patients, while Ikeda confirmed its presence in systemic
]. Thrombi formation is often an opportunistic
event precipitated by environmental factors, and we,
therefore, speculate that this partially explains the 1/150
At present, it is highly probable that inflammatory
signals trigger MMD. However, there has been no
epidemiological evidence on the association of infection histories
or other life-style or behavior factors with MMD in the
carriers. Epidemiological evidence obtained through cohort
studies focusing on carriers is deficient at present and is
Several studies have shown that the ablation of RNF213
does not cause deleterious effects on angiogenesis, except
in zebrafish [
12, 20, 61
], suggesting that it might not affect
mammalian species. A promising hypothesis is that
RNF213 R4810K causes MMD by a dominant negative or
gain-of-function mechanism. If this is the case, a
pharmacological antagonist that inhibits ATP binding to the
Walker A motif would be a suitable candidate as a drug
RNF213 R4810K carriers have a very high prevalence in
Japan and Korea (1–2 %) and are extremely likely to
develop MMD. At present, however, there are insufficient
data to predict the health risk of the carriers, except for
subjects of familial MMD. It is, therefore, important to
obtain carrier data and to elucidate the MMD risk
attributable to RNF213 R4810K. In parallel, public health
researchers should collaborate with genetic counsellors to
facilitate genetic risk communication, not only to carriers,
but also to society to avoid the social discrimination of
carriers. A great deal of uncertainty currently surrounds
application of genetic testing to the general population;
indeed, it may have no benefit for the general population
and only limited benefit for unaffected members in familial
cases with MMD.
MMD was first described in 1957 by Takeuchi and Shimizu
]. Although genetic factors had long been speculated, the
angiographic definition of the MMD likely misled its genetic
analysis. Recently, RNF213 R4810K was identified as the
major susceptibility gene [
], and full-length cDNA
cloning, iPS technology, and animal models have enabled
the pathological roles of RNF213 R4810K to be investigated.
Systemic biomedical and genetic epidemiology studies with
specific emphasis on carriers will provide a deep
understanding not only of MMD but also of associated health and
environmental risk factors. Furthermore, such research will
lead to a novel disease definition than the present one, and
pave the way for new preventive strategies for
cerebrovascular diseases, especially those in children.
Acknowledgments This work was supported by a Grant from the
Ministry of Education, Culture, Sports, Science, and Technology of
Japan (No. 25253047). It was partially supported by a Grant from the
Ministry of Education, Culture, Sports, Science, and Technology of
Japan (No. 15K19243), and a Grant from the Research Committee on
Spontaneous Occlusion of the Circle of Willis of the Ministry of
Health and Welfare of Japan (No. H26-Nanjito-Ippan-078).
Compilance with ethical standards
Conflicts of interest Prof. Koizumi and Dr. Hitomi have a patent
JP2010068737 pending regarding with MMD. Other authors declare
that they have no conflicts of interest.
Human and animal rights statement This article does not contain
any studies with human participants or animals performed by any of
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://creative
commons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link
to the Creative Commons license, and indicate if changes were made.
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