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2016 - Garcia‐Quintanilla.pdf
1. Insights & Perspectives
Extraintestinal manifestations of
celiac disease: 33-mer gliadin binding
to glutamate receptor GRINA as a
new explanation
Albert Garcia-Quintanilla* and Domingo Miranzo-Navarro
We propose a biochemical mechanism for celiac disease and non-celiac gluten
sensitivity that may rationalize many of the extradigestive disorders not
explained by the current immunogenetic model. Our hypothesis is based on the
homology between the 33-mer gliadin peptide and a component of the NMDA
glutamate receptor ion channel – the human GRINA protein – using BLASTP
software. Based on this homology the 33-mer may act as a natural antagonist
interfering with the normal interactions of GRINA and its partners. The theory is
supported by numerous independent data from the literature, and provides a
mechanistic link with otherwise unrelated disorders, such as cleft lip and palate,
thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss,
fibromyalgia, dermatitis herpetiformis, schizophrenia, toxoplasmosis, anemia,
osteopenia, Fabry disease, Barret’s adenocarcinoma, neuroblastoma, urinary
incontinence, recurrent miscarriage, cardiac anomalies, reduced risk of breast
cancer, stiff person syndrome, etc. The hypothesis also anticipates better
animal models, and has the potential to open new avenues of research.
Keywords:
.celiac disease; cleft lip and palate; dermatitis herpetiformis; gluten ataxia;
GRINA; osteopenia; thyroid
Introduction
Dietary gluten is found in wheat and
other cereals such as barley, rye, spelt,
or triticale, and represents up to 90% of
the grain protein-content. According to
their solubility in aqueous alcohols,
gluten proteins are divided into insolu-
ble aggregated glutelins and soluble
monomeric prolamins. Wheat gluten,
the most studied, consists of the glutelin
glutenins and the prolamin gliadins
(which are further classified into a/b,
g, and v-type, depending on their
electrophoretic motility) [1]. Both frac-
tions contain numerous motifs involved
in mucosal damage and the immune
response in celiac disease (CD) [2], and
are usually rich in glutamine (Q) and
proline (P) residues.
The current theory for CD
CD affects around 1% of the population
and is defined as a chronic small intestinal
immune-mediated enteropathy precipi-
tated by exposure of genetically predis-
posed individuals to dietary gluten [3].
According to the current immunoge-
neticmodelofCD,somegliadinfragments
are able to resist proteolytic degradation
when gluten is ingested. Alpha-gliadin
contains two regions (p111–130 and p151–
170) that can bind to CXCR3 receptors
and promote the release of zonulin by
cells. Zonulin provokes the opening of
the tight junctions between cells, allow-
ing other gliadin peptides to cross the
gut barrier and reach the lamina propria
[4]. Once there, the cytotoxic p31–43
peptide mediates the innate immune
response by upregulating the release of
IL-15. This cytokine also stimulates intra-
epithelial lymphocytes [5]; while the
p261–277 peptide promotes IL-8 chemo-
kine expression and contributes to the
inflammatory response [4].
The gliadin fragments can be deami-
dated by intracellular or extracellular
tissue transglutaminase (tTG, also known
as TG2), or, to a lesser extent, they can be
DOI 10.1002/bies.201500143
Department of Biochemistry and Molecular
Biology, School of Pharmacy, University of Seville,
Spain
*Corresponding author:
Albert Garcia-Quintanilla
E-Mail: AlbertGQ1970@us.es
Abbreviations:
AGA, anti-gliadin antibodies; anti-EMA, anti-
endomysial antibodies; CD, celiac disease;
DGP, deamidated gliadin peptides; ER, endoplas-
mic reticulum; NCGS, non-celiac gluten sensitiv-
ity; tTG, tissue transglutaminase.
www.bioessays-journal.com 427
Bioessays 38: 427–439, ß 2016 WILEY Periodicals, Inc.
Hypotheses
2. transaminated and remain linked to the
tTG. In particular, tTG converts specific Q
residues (with neutral charge) into glu-
tamic acid (E) (with negative charge).
Deamidated gliadin peptides (DGP)
engulfed by antigen-presenting cells are
then recognized with increased affinity
byHLA-DQ2orHLA-DQ8haplotypes,and
presented on their surface to CD4 T cells.
This initiates the adaptive immune re-
sponse in which T cells contribute to
chronic inflammation and B cells gener-
ate either anti-gliadin antibodies (AGA),
antibodies against DGP (anti-DGP), anti-
tTG antibodies (triggered by tTG bound
to gliadin fragments), or anti-endomysial
antibodies(anti-EMA,alternativelycalled
anti-EAE) that also target tTG found in
the damaged intestinal lining.
Role of the 33-mer in the
development of CD
The 33-mer peptide (p57–89) from the
a2-gliadin subtype is the main compo-
nent responsible for the adaptive im-
mune response against gluten [4, 6]. It
has been found in early endosomes from
CD patients, but not in late endosomes,
hence suggesting that it escapes from
lysosomal degradation [7]. It contains
three consecutive PQLPYPQ sequences
that account for a total of six over-
lapping epitopes [8] (Fig. 1) which can
be recognized by HLA-DQ2 alleles.
Homologs of this 33-mer peptide are
found in all grains (except oats) that
affect CD patients, but are absent in all
unreactive food grains [10]. Deletion
mutants excluding the 33-mer sequence
are not reactive either [10].
Prevalence and manifestations
of CD and NCGS
According to Marsh [3], CD patients are
classified into four groups depending on
the level of their intestinal histopatho-
logical lesions: class 0 (normal), class I
(infiltrative), class II (hyperplasic), and
class III (atrophic), the last of which is
further divided into IIIa for mild atro-
phy, IIIb for moderate atrophy, and IIIc
for total atrophy.
In European populations, up to 90%
of CD patients bear HLA-DQ2 haplo-
types, while the remaining mostly have
HLA-DQ8 alleles. However, other ge-
netic risk markers have been described
as well [11, 12], and HLA frequencies are
different in other parts of the world [13].
Non-celiac gluten sensitivity (NCGS)
occurs at a higher frequency than CD.
It is precipitated by the ingestion of
gluten in people in whom CD has been
excluded, with no signs of enteropathy
and variable AGA [3]. On the other
hand, atypical CD is used to describe
patients without malabsorption but with
extraintestinal manifestations, such as
thyroid dysfunction, depression, gluten
ataxia, reproductive disease, dermatitis
herpetiformis, or skeletal findings. In
most cases, symptoms disappear with a
gluten-free diet, except for refractory
disease, where damage is irreversible.
The current immunogenetic
model does not explain all
cases of CD and NCGS
The current immunogenetic model for
CD does not clarify many of the extra-
digestive disorders related to CD [14, 15]
and NCGS [16]. HLA-DQ2 and HLA-DQ8
are the main contributors to CD. They
are necessary, but not sufficient, for the
manifestation of CD, and cannot predict
its development, because 40–65% of
first-degree healthy relatives have them
[13]. Furthermore, around 30% of the
Caucasian population in general pos-
sesses these HLA serotypes [11]. Cur-
rently, genetic variation only explains
31% of the CD heritability [11], and half
of the patients with NCGS do not have
HLA-DQ2 or HLA-DQ8 alleles [17], which
is somewhat similar to the percentage
found in the general population [16].
Classic presentations of CD with
gastrointestinalsymptomsaremoreprev-
alent in children (80%), whereas atypical
forms are more frequent in adults
(85%) [18]. Anti-tTG antibody is the most
specific and sensitive serologic test avail-
able for diagnosing CD. This antibody is
positive in about 90% of children with
CD as compared to 30% of adults [18, 19],
and its levels positively correlate with
the extent of villous atrophy and the
Marsh classification. In contrast, no anti-
tTG, anti-EMA, or anti-DPG antibodies
are seen in NCGS patients, and only 50%
of such patients are positive for AGA [3].
Taken together, these findings
strongly suggest that in addition to the
immunological mechanism, additional
mechanisms may explain extradigestive
manifestations in CD and NCGS subjects
with absent or minor intestinal damage,
and absence of anti-tTG antibodies, and
also in NCGS patients without HLA-DQ2
or HLA-DQ8 alleles. As a result, some
authors have proposed additional hy-
potheses [20, 21].
A new biochemical theory
for CD based on
non-immunological
interactions of the 33-mer
Here we propose a new biochemical
mechanism, supplementary to the current
immunogenetic model, that is based on
the homology found between the 33-mer
Figure 1. Homology between the 33-mer gliadin fragment (P18573.1) and GRINA from
different species using BLASTP 2.2.32þ program [9]. The six overlapping epitopes within the
33-mer peptide are shown on top. The homologous region of human GRINA contains four
repetitive sequences, namely PYPQ[G/E]GYPQG, shown in color, and a total of seven ALK
kinase domain substrate binding motifs (YxxxxY) evenly spread.
A. Garcia-Quintanilla and D. Miranzo-Navarro Insights & Perspectives.....
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3. gliadin fragment and the human protein
GRINA using the BLASTP 2.2.32þ pro-
gram [9] (Fig. 1).
Up to 40% of all protein interactions
may be mediated by peptides [22], and,
it has been shown that peptides derived
from the interface domains of interact-
ing proteins could inhibit their inter-
actions by mimicking the mode of
binding to the cognate partners [23].
The 33-mer gliadin fragment
acts as a natural antagonist,
interfering with GRINA and its
interacting partners
According to our model, the 33-mer
peptide would act as a natural antago-
nist, interfering with GRINA and its
interactome (the whole set of molecules
that interact with the protein) due to
its homology with a region in the N-
terminal domain of GRINA.
The 33-mer folds into a polyproline II
(PPII) helix that is favorable for protein–
protein interactions (Fig. 2), but at higher
local concentrations it can also adopt
supramolecular structures such as nano-
spheres or parallel b-sheet structures [25].
Meanwhile, GRINA (also called TMBIM3)
is able to form homo-oligomers [26],
similarly to other members of the TMBIM
family [27], or hetero-oligomers with
TMBIM6 [26]. An analysis of the predicted
secondary structure of the N-terminal
region of GRINA using s2D software [24]
shows that it may fold into a PPII helix
(Fig. 2), making the interaction with the
33-mer PPII helix very likely to occur
(collagenisthemost commonexampleof
a triple PPII helix).
Two kinds of interactions with the
33-mer are hypothesized (Fig. 3): 1) the
33-mer interacts directly with the ho-
mologous N-terminal region of GRINA,
disrupting its oligomerization and re-
lated functions; 2) the 33-mer interacts
with GRINA’s partners and alters their
functions.
The first interaction is based on the
homologybetweenGRINAand33-mer,and
its consequences could also be explained
by an autoimmune mechanism against
GRINA, if this truly exists; the second kind
of interaction is based on complemen-
tarity, and therefore its effects are hard
to explain by an immune mechanism.
According to our hypothesis, if the
extradigestive manifestations found in
CD and NCGS are due to the interactions
between the 33-mer and GRINA or its
binding partners, then we should be
able to observe similar phenotypes
when disrupting such genes (either
using knock-outs, interfering RNAs
or drugs), and find that their expression
is altered in these patients, if studied.
Pursuant to this thinking, we ana-
lyzed the interactome of GRINA using
two independent softwares, String v9.1
[28] and FunCoup 3.0 [29], with the aim
of ascertaining whether the alteration of
these genes had any phenotype linked
to extradigestive (atypical) CD or NCGS.
We should mention that while writing
this article a new algorithm, String
v10 [30], has been released, which
reveals new interactions.
Before describing the main evidence
of our hypothesis it is necessary to
explain GRINA and its interactome.
Structure and function of
GRINA
GRINA is mainly expressed in testis,
kidney, and the central nervous system
(with higher levels in the cerebellum)
[26, 31]. At the cellular level it has been
reported mostly in the Golgi, but also
in the endoplasmic reticulum (ER) [26,
31, 32]. This relates to its involvement
in endosome-to-Golgi retrieval [33], a
process that is important for membrane
trafficking, and which is linked to
neurodegeneration. In this sense, GRINA
is also involved in glutamate receptor
signaling in neurons [34], hence its
alternative name is NMADARA1 (NMDA
Receptor-Associated protein 1). Lastly,
GRINA also participates in ER calcium
homeostasis. Under ER stress condi-
tions it is upregulated and its expres-
sion reduces inositol1,4,5-triphosphate
Figure 2. Predicted structures of the 33-mer gliadin fragment (top) and N-terminal region of
GRINA using s2D software [24]. Both sequences show propensity to form polyproline II helix
(PPII) making interaction with each other very likely.
.....Insights & Perspectives A. Garcia-Quintanilla and D. Miranzo-Navarro
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4. (IP3)-mediated ER calcium release to
the cytosol, thus promoting cell survival
[26, 31, 35]. For this reason, is has been
termed “lifeguard 1” (LFG1).
At the structural level, GRINA has a
cytoplasmic N-terminal region with ho-
mology to the 33-mer gliadin fragment
followed by seven transmembrane
domains that contain the transmem-
brane BAX inhibitor motif (TMBIM) [31,
35].ItscharacteristicsareshowninFig.4.
Interactome of GRINA
The known interactome of GRINA is
shown in Table 1 and the genes are
explained in more detail under the
extraintestinal manifestations in which
they are involved. Additional binding
partners may arise from future research
and software releases.
Extradigestive
manifestations in CD and
NCGS: Linking diseases
with the interactome of
GRINA
Table 2 shows a list of extraintestinal
disorders somehow connected to CD and
NCGS that are explained or predicted by
this hypothesis. Below, we briefly de-
scribe the effects of GRINA and its
interactome that justify this hypothesis,
providing a unifying explanation for
otherwise unrelated findings.
Laboratory findings
AMN inhibition hinders vitamin B12
absorption
Vitamin B12 and folic acid deficiencies
are found in 20% of newly diagnosed CD
patients, respectively [41]. Vitamin B12
plays a central role in cell metabolism
and it is important in the maintenance
of the central nervous system. The
most common symptom of vitamin B12
deficiency is numbness and tingling
in the hands and feet. AMN interacts
with the cubilin protein to form the
cubam receptors in the ileum [42]
that are responsible for almost all
of the vitamin B12 absorbed by the
organism. Therefore, its inhibition may
cause vitamin B12 deficiency. This
deficiency can be masked by folate
supplementation.
Deregulation of SREBF2 may provoke
low cholesterol levels
SREBF2 is a transcription factor that
controls cholesterol homeostasis. In the
presence of cholesterol this transmem-
brane protein is located in the ER
(similarly to GRINA), bound to other
ligands. However, in the absence of
cholesterol, it travels to the Golgi, from
where the actual transcription factor is
processed and released to enter the
nucleus. Once there, it stimulates en-
dogenous synthesis of cholesterol and
the extracellular uptake. According to
our model, SREBF2 may be deregulated
in CD because patients usually have
lower cholesterol levels [43–45].
Low proportion of long chain fatty acids
may be due to ACSL1 deregulation
ACSL1 plays a key role in the activation
of long chain fatty acids for their
subsequent degradation or synthesis
of cellular lipids. Interestingly, it has
been shown that the proportion of long
chain fatty acids is lower in CD patients
than in disease-free individuals [46],
which suggests that ACSL1 may be
deregulated.
Endocrine
Thyroid dysfunction may be due to
WBP2 and thyroglobulin deregulation
WBP2 (WW domain binding protein 2)
contains a WW domain that mediates
interactions with polyproline ligands.
This may enable the 33-mer fragment
to interact with WBP2, interfering with
its natural targets. One of them is
the transcription factor Pax8, which is
specific for the thyroid gland [47]. Pax8
is required in the morphogenesis of
the thyroid gland and is involved in the
regulation of thyroid-specific genes,
such as thyroglobulin.
The TG gene codes for thyroglobulin
(the precursor of the thyroxine hormone
produced in the thyroid gland) and is
located on chromosome 8 (8q24.22),
similarly to GRINA (8q24.3). CD patients
have a higher incidence of thyroid
dysfunction [15, 43] and a shorter
stature than average. Thyroxine defi-
ciency can provoke shorter stature and
reduce cerebral and reproductive devel-
opment, and this could be explained in
part by the presence of anti-tTG anti-
bodies that can bind the thyroid follicles
and the extracellular matrix. However,
more than half of such patients have
Figure 3. Possible interactions between the 33-mer gliadin fragment and GRINA and its
ligands under conditions of dietary intake of gluten in susceptible individuals. Interaction of
the 33-mer fragment with GRINA may disrupt oligomerization or binding with its partners.
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5. no anti-tTG antibodies [15, 48], hence
supporting the existence of alternative
mechanisms.
ACSL1 may be involved in metabolic
syndrome
ACSL1 expression negatively correIates
to insulin resistance and central obe-
sity [49], both common traits of meta-
bolic syndrome. Resolution of metabolic
syndrome after initiation of a gluten-
free diet in a CD patient has been
described [50].
Reproductive
TMEM14C inhibition results in
embryonic death
Recurrent miscarriage is common in CD
and NCGS [51]. Gliadin has been found
in abundance in extravillous tropho-
blasts of noncompliant CD pregnant
women [52]. Extravillous trophoblasts
are essential for attachment of the
placenta to the mother, but also to
allow adequate blood supply to the
fetus during pregnancy. Inhibition of
TMEM14C by the 33-mer could be
involved, because TMEM14C deficiency
in mice results in embryonic lethality
due to profound anemia [53]. Deuter-
oporphyrin IX (a synthetic protoporphy-
rin analog), but not iron, has been
shown to considerably complement
TMEM14C defect, and could represent
a new strategy to increase survival.
Developmental
Cleft lip and palate may also be due to
inhibition of CLPTM1 and AMN
Disruption of the CLPTM1 gene provokes
cleft lip and palate in humans [54].
This anomaly affects one or two new-
borns per thousand births. It has been
proposed that maternal CD may be
involved in some cases [55]. Maternal
folate supplementation can reduce oro-
facial clefts [56]. However, an alterna-
tive explanation is that the 33-mer
gliadin fragment may be able to reach
the placenta through the bloodstream
[52], cross it and interfere with the
unborn fetus’ normal CLPTM1 function.
It has been reported that gliadin affects
the fetal part of the placenta, causing
affected children to be small for their
age [52]. Accordingly, children with cleft
lip and palate have lower weight than
normal [57, 58].
Vitamin B12 is a required cofactor of
the methionine synthase. This enzyme
is at the intersection of the cellular
methylation cycle and the folate cycle,
detoxifying homocysteine to regenerate
the amino acid methionine (which is
part of a cofactor needed for the
production of several neurotransmit-
ters), and tetrahydrofolate (THF) (which
is the active form of folic acid). THF
is also produced by the dihydrofolate
reductase (DHFR) enzyme from ingested
folic acid. Developmental inhibition of
DHFR results in changes in the embry-
onic mouth that resemble cleft lip and
palate [56], increasing cell death via
DNA damage. In contrast, the 33-mer
may well interfere with AMN, impairing
vitamin B12 absorption. In such cases,
vitamin B12 deficiency can produce a
pseudo folate deficiency if THF is not
restored, whereas homocysteine accu-
mulation can trigger ER stress, activa-
tion of glutamate receptors, and DNA
damage, leading to apoptotic cell death.
In support of this alternative, a signifi-
cant role of the methylation cycle and
methionine synthase in the develop-
ment of cleft lip and palate has been
identified in humans [59].
Dermatological
Inhibition of GRINA and TMBIM6 may
increase autoantibodies in dermatitis
herpetiformis (DH)
Transglutaminase antibodies are char-
acteristic in DH; however a study with
immunodeficient mice that received
sera from DH patients suggested that
circulating antibodies are not patho-
genic alone [60]. Using a transgenic
mouse model of DH, other authors
Figure 4. General structure of human GRINA, showing the seven transmembrane domains
and the N-terminal region facing the cytoplasm. Proline residues are colored in red, and the
region with homology to the 33-mer gliadin fragment is shown in green. The N-terminal
region has 164 residues and is the longest of the TMBIM family [26]. It contains several
potential signaling motifs that can be phosphorylated [36]. The signaling sequences include,
among others, a G protein-coupled receptor kinase 1 substrate motif (MSHEKS) at the
beginning of the N-terminal; the NPxY motif [33] required for efficient ligand-mediated
receptor internalization and biological signaling [37]; the sorting FLV motif involved in
endosome-to-Golgi retrieval [32, 38]; a number of YxxP motifs that bind SH2 domains [39];
and several SP motifs recognized by the glycogen synthase kinase-3 (which is involved in
glucose homeostasis, Alzheimer’s and other diseases), that can interact with triple-stranded
b-sheet WW domains as well. GRINA also contains an EGFR kinase substrate motif in its
sixth intermembrane region (facing the same side as the N-term domain where the 33-mer
binds). The graph was generated using Protter v1.0 [40].
.....Insights & Perspectives A. Garcia-Quintanilla and D. Miranzo-Navarro
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6. found similar results [15], proposing
that transglutaminase antibodies may
not be sufficient by themselves for the
pathology to occur.
Deamidation and crosslinking of the
33-mer peptide occurs in the gut by tTG,
resulting in autoantibodies that cause
CD. Similarly to tTG, TG3 (present in the
skin) is able to form a complex with
the 33-mer fragment, although less effi-
ciently, thus triggering autoantibodies
that are involved in DH. Both tTG and
TG3 can be detected on the cell surface
and inside the cytosol. Interestingly,
all of them are calcium-dependent
crosslinkers. As cited above, GRINA
plays a role in calcium homeostasis,
together with TMBIM6, negatively mod-
ulating the release of ER calcium by
the inositol 1,4,5-triphosphate receptor
(IP3R), thus decreasing calcium-mediated
cell death. Therefore, deregulation of
calcium homeostasis may be an underly-
ing condition contributing to tTG and
TG3 overactivation, increased crosslink-
ing and autoimmunity.
HSP90 may be involved in DH
HSP90 is a chaperone that assists other
proteins for their correct folding. Anti-
bodies against HSP90 have been
detected in patients with DH [61], and
their levels correlate with those of anti-
tTG antibodies. This suggests that the
33-mer fragment may be able to bind to
HSP90, and in some cases be attached
to it by the cytosolic tTG, allowing the
generation of autoantibodies.
PUF60 may be involved in
dermatomyositis
Dermatomyositis is a rare inflammatory
disease characterized by muscle weak-
ness and a distinctive skin rash. Anti-
bodies against PUF60, a protein involved
in alternative splicing of genes, have
been detected in these patients [62], and
complete resolution of dermatomyositis
has been described in a CD patient after
a gluten-free diet [63]. Remarkably,
dermatomyositis patients have increased
tTG levels [64], which may contribute to
the generation of autoantibodies against
PUF60 by possibly linking the 33-mer
fragment and PUF60 together.
KRTAP5-6 might be involved in
alopecia
KRTAP5-6 is expressed in hair roots but
not skin and is vital for healthy hair
shape. However, its involvement in
alopecia seen in CD patients, has not
yet been substantiated.
Infectious
MLF2 inhibition confers sensitivity to
Toxoplasma infection
A recent study has shown that CD
increases the risk of Toxoplasma infec-
tion in pregnant women [65]. Although
the common explanation for such risk
is a “leaky gut,” this alternative hypo-
thesis proposes that the inhibition of
MLF2 by the 33-mer fragment may
be the underlying cause. Disruption of
the MLF2 gene confers sensitivity to the
intestinal parasite Toxoplasma gondii
[66], provoking diarrhea.
Musculoskeletal
WBP2, AMN, and TMEM14A inhibition
may provoke lowered mineral bone
density
Up to 75% of CD patients have reduced
mineral bone density, osteopenia, or
osteoporosis, independent of serological
markers, age or digestive symptoms [67].
Accordingly, female mice lacking the
WBP2 gene suffer a lower mineral bone
density. Recently, a role of vitamin B12 in
bone mineral density of men treated for
CD has been reported [68], which could
Table 1. Interactome of GRINA using String v9.1 [28] and FunCoup 3.0 [29]
Name Description
TMBIM6 Transmembrane BAX inhibitor motif containing 6; suppressor of apoptosis
WBP2 WW domain binding protein 2
TG Thyroglobulin
CLPTM1 Cleft lip and palate associated transmembrane protein 1
NAPA N-ethylmaleimide-sensitive factor attachment protein, alpha
ATP6V0C; ATP13A1 ATPase, Hþ transporting, lysosomal 16kDa, V0 subunit c; ATPase type 13A1
MLF2 Myeloid leukemia factor 2
ENSG00000233536 Long non-coding RNA PIWIL4-1:3
PUF60 Poly-U binding splicing factor 60KDa
NOMO2; NOMO3 NODAL modulator 2; NODAL modulator 3
SREBF2 Sterol regulatory element binding transcription factor 2
TMEM14A; TMEM14B; TMEM14C Transmembrane protein 14A; Transmembrane protein 14B; Transmembrane protein 14C
ACSL1 Acyl-CoA synthetase long-chain family member 1
SLC25A3; SLC6A1 Solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3; Solute carrier
family 6 (neurotransmitter transporter, GABA), member 1
HSP90AA1; HSP90AB1 Heat shock protein 90 kDa alpha (cytosolic), class A member 1; Heat shock protein
90 kDa alpha (cytosolic), class B member 1
KRTAP5-6 Keratin associated protein 5–6
GRID1; GRIA1 Glutamate receptor, ionotropic, delta 1; Glutamate receptor, ionotropic, AMPA 1
GSTO2 Glutathione S-transferase omega 2
AMN Amnionless homolog (mouse)
DGKD Diacylglycerol kinase, delta 130 kDa
In bold, new interactions released by the String v10 software [30].
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7. be due to AMN inhibition by the 33-mer
peptide.AMNmayalsoactasaco-receptor
of bone morphogenetic proteins – which
induce cartilage and bone formation –
hence modulating their signaling path-
way. Likewise, a genome-wide associa-
tion study using samples from more than
a thousand patients found that knock-
down of TMEM14A alters the expression
of genes related to osteoporosis [69].
Accordingly, inhibition of bone morpho-
genic proteins by the 33-mer may repre-
sent a hitherto unidentified pathological
mechanism in addition to intestinal
malabsorption, and may open new
avenues for treatment.
Rheumatological
Glutamate receptors may be
deregulated in fibromyalgia
Glutamate levels are higher in patients
with fibromyalgia [70]. A study shows
that fibromyalgia symptoms disappeared
in patients with no anti-tTG antibodies
following a gluten-free diet [71], and a
more extensive work suggests that a
subpopulation of fibromyalgia patients
could have subclinical CD or NGCS [72].
Hence it is feasible that dietary gluten
leads to the deregulation of glutamate
receptors GRINA, GRID1, and GRIA1 in
susceptible individuals.
PUF60 may be involved in Sj€
ogren’s
syndrome
Sj€
ogren’s syndrome patients usually
have dry eyes and dry mouth. Anti-
bodies against PUF60 are found in
30% of Sj€
ogren’s syndrome patients
[62], suggesting its involvement in the
pathology.
Oncological
Inhibition of the cellular antioxidant
GSTO2 may increase the risk of
developing small intestinal
malignancies and Barret’s
adenocarcinoma
Glutathione S-transferases (GST) trans-
fer glutathione (an important cellular
antioxidant) to xenobiotics for their
detoxification and breakdown, confer-
ring protection against carcinogenesis.
GSTs have been found to be signifi-
cantly lower in untreated CD patients
compared to controls [73], which may
explain in part the increased risk of
developing small intestinal malignan-
cies in untreated CD. In particular,
GSTO2 has been associated with Barret’s
adenocarcinoma [74]. Therefore GSTO2
could be inhibited by the 33-mer.
DGKD overexpression may be involved
in epithelial cancer
On the contrary, DGKD expression has
been found to be increased in small
intestinal mucosal epithelial cells of
untreated CD patients [75], together
with other genes involved in the epider-
mal growth factor receptor (EGFR)
signaling pathway. EGFR is deregulated
in CD [5] and upregulation of the EGFR
pathway has been associated, in partic-
ular, with epithelial cancers (while its
inhibition provokes a papulopustular
rush [76] that resembles dermatitis
herpetiformis).
Table 2. Extraintestinal manifestations connected to CD and NCGS explained or
predicted by this hypothesis
Manifestations Predicted biochemical interactions
Laboratory findings
Vitamin B12 deficiency AMN
Low cholesterol SREBF2
Low ratio of long chain fatty acids ACSL1
Endocrine
Thyroid disease WBP2 (Pax8); TG
Metabolic syndrome ACSL1
Reproductive
Recurrent miscarriage TMEM14C
Developmental
Cleft lip and palate CLPTM1; AMN; WBP2 (YAP)
Dermatological
Dermatitis herpetiformis GRINA; TMBIM6; HSP90
Dermatomyositis PUF60
Alopecia KRTAP5-6
Infectious
Toxoplasmosis MLF2
Musculoskeletal
Osteopenia; Osteoporosis WBP2; AMN; TMEM14A
Rheumatological
Fibromyalgia GRINA; GRID1; GRIA1
Sj€
ogren’s syndrome PUF60
Oncological
Barret’s adenocarcinoma GSTO2
Small intestinal malignancies GSTO2; DGKD
Myeloid leukemia MLF2
Reduced risk of breast, endometrial,
and ovarian cancer
WBP2 (TAZ, YAP)
Neurological
Peripheral neuropathy AMN
Restless legs syndrome WBP2 (WWC2)
Epilepsy SLC6A1
Spinocerebellar ataxia GRINA; TMBIM6
CEC syndrome GRINA; TMBIM6
Stiff person syndrome GABARAP
Limbic encephalitis GRIA1
Opsoclonus mioclonus GRINA
Neuroblastoma GRINA
Psychiatric
Major depression GRINA
Schizophrenia GRID1
Other
Hearing loss WBP2 (YAP); GRID1
Fabry disease GRINA (Gb3 synthase)
Female urinary stress incontinence SLC6A1
Verheij syndrome PUF60; GRINA
Cardiac anomalies HSP90AA1; AMN
Hypertrophic cardiomyopathy SLC25A3
.....Insights & Perspectives A. Garcia-Quintanilla and D. Miranzo-Navarro
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8. MLF2 may be involved in myeloid
leukemia
MLF2 (myeloid leukemia factor 2) is so-
named because of its association with
myeloid leukemia. CD patients have an
increased risk of developing lymphoma,
which may (at least partly) be a result of
the gliadin 33-mer binding to MLF2.
However, only three cases of acute
myeloid leukemia and CD have been
described in the literature [77].
Inhibition of WBP2 may explain the
lower risk of breast, endometrial, and
ovarian cancer in CD
WBP2 binds to the main effectors of the
Hippo pathway, the oncogenes TAZ [78],
and its paralog YAP [79]. It also acts as
a coactivator of estrogen receptors [80]
and is important for the development of
breast cancer [81, 82]. Knockdown of
WBP2 suppresses TAZ-driven transfor-
mation, while its overexpression enhan-
ces it [78]. Interestingly, a reduced risk
of breast, endometrial, and ovarian
cancer in women with CD has been
reported [83], hence suggesting that
the 33-mer fragment may inhibit WBP2
activity. Also, loss-of-function mutations
in YAP provoke hearing loss, cleft lip and
palate, intellectual disability, hematuria,
and eye coloboma [84], which further
supports that WBP2 is inhibited by the
33-mer fragment.
Neurological
Peripheral neuropathy may be caused
by AMN inhibition
Up to 40% of CD patients may develop
peripheral neuropathy [85]. A potential
cause of tingling and numbness in
hands and feet is vitamin B12 deficiency,
which can precede CD diagnosis and is
commonly found in newly diagnosed
patients [41]. As we discussed before,
AMN impairment by the 33-mer may
lead to vitamin B12 malabsorption.
WWC2 may be involved in restless legs
syndrome
Incidence of restless legs is higher in CD
patients [86, 87] and has traditionally
been assigned to iron deficiency [88].
However, 60% of the restless legs cases
in CD patients show no iron deficiency
[86]. Also, no difference in AGA, anti-
EMA, and anti-tTG antibodies was seen
in a study with almost one hundred
cases of restless legs versus controls
[89], supporting the notion that differ-
ent mechanisms other than immuno-
logical may be involved. WWC2 is one of
the four potential candidates involved
in restless legs syndrome [90]. Interest-
ingly, WWC2 interacts with WBP2, and
both contain WW domains that are
involved in the union of proline-rich
ligands; GRINA has four WW domain
binding motifs in its N-terminal domain,
one within the 33-mer homology region.
GABA transporter 1 (GAT-1) may be
inhibited in epilepsy
Similarly to GRINA, GAT-1 is also a
transmembrane protein. Therefore, it is
possible that both interact transiently
and that the 33-mer may interfere with
such an interaction. GAT-1 removes
GABA from the synapse and is encoded
by SLC6A1. Inactivating mutations in
SLC6A1 cause epilepsy [91] and 33-mer
inhibition of GAT-1 might also have the
same effect in CD patients. However, the
association between epilepsy and CD is
still under discussion.
Inhibition of GRINA and TMBIM6 may
increase autoantibodies in
spinocerebellar ataxia
IP3Randotherproteinsrelatedtocalcium
signaling may be involved in spinocer-
ebellar ataxia [92]. A recent article
showed that gliadin peptides can trigger
ER stress in the immortalized cell line
Caco-2 (derived from human colorectal
carcinoma) through calcium mobiliza-
tion [93]. As mentioned above, inhibition
of GRINA and TMBIM6 by the 33-mer may
favor the release of ER calcium to the
cytosol by IP3R, making it available to
thecalcium-dependentcrosslinkerTG6(a
transglutaminase abundantly expressed
in the central nervous system). Thus,
deregulation of calcium homeostasis
might represent a causal mechanism that
contributes to TG6 overactivation.
GRINA and TMBIM6 may be involved in
brain calcifications and CEC syndrome
Calcium deregulation may lead to calci-
fications in the brain. CEC syndrome is a
rare combination of CD, epilepsy, and
cerebral calcification [94, 95]. Therefore
inhibition of GRINA and TMBIM6 should
be suspected.
GABARAP inhibition may be involved in
stiff person syndrome
There is a high prevalence of NCGS
with stiff person syndrome [96], a
neurologic disorder characterized by
progressive rigidity and spasms. Up to
65% of these patients have antibodies
that inhibit GABA-receptor associated
protein (GABARAP) on GABAergic neu-
rons [97]. GABARAP has been described
as part of the mouse GRINA interac-
tome and could be inhibited by the
33-mer in non-compliant CD and NCGS
patients. Several cases of stiff person
syndrome have been described in
coexistence with CD, NCGS, diabetes,
ataxia, or DH [96, 98, 99].
GRIA1 is associated with limbic
encephalitis
GRIA1 mutations have been associated
with limbic encephalitis [74]. A case of
limbic encephalitis and CD has been
reported [100].
Anomalous phosphorylation of GRINA
may be associated to opsoclonus
myoclonus (OM) and neuroblastoma
Half of OM cases (also known as
dancing eyes, dancing feet syndrome)
occur in children with neuroblastoma
[101]. A case of OM associated with CD
has been described [102]. ALK plays a
key role in the development of the brain
and is involved in neuroblastomas [103].
As mentioned before, GRINA has seven
ALK kinase domain substrate motifs
evenly spread in the homology region
with the 33-mer (Fig. 1). Accordingly,
the 33-mer may hinder its phosphory-
lation by ALK kinase.
Psychiatric
Overexpression of GRINA is involved in
major depression
Around 40% of CD patients suffer major
depression [104]. Experts suggest that
alterations of glutamate neurotransmis-
sion may be involved. In agreement
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9. with this idea, a study analyzing 200
genes identified GRINA as one out of
four genes overexpressed in patients
with major depression [105].
GRID1 is associated with schizophrenia
CD and NCGS patients have an in-
creased risk of schizophrenia [106].
Mutations in the glutamate receptor
GRID1 have been associated with
schizophrenia [107] and may provide
the link between the two diseases. Also,
only a proportion of the cases occur
with positive serum biomarkers [108].
Other manifestations
Inhibition of WBP2 or GRID1 causes
hearing loss
Several studies have shown a higher
prevalence of hearing loss in CD patients
[109–112]. Mice lacking either the
WBP2 [113] or GRID1 [114] gene experi-
ence hearing loss, hence suggesting that
inhibition of these proteins by the 33-mer
may provoke hearing loss in humans.
Deregulation of GRINA may be involved
in Fabry disease
Accumulation of globotriaosylceramide
(Gb3) causes Fabry disease, a metabolic
disorder caused by a defect in lysosomal
storage. Interestingly, GRINA is involved
in the regulation of Gb3 [115], and a
clinical case of improvement in Fabry
disease after a gluten-free diet has been
reported [116], hence supporting the
suggestion that GRINA may be altered.
Inhibition of SLC6A1 may cause female
urinary stress incontinence
Urinary stress incontinence is common
in CD patients accidentally exposed to
gluten. SLC6A1 has been associated
with female urinary stress incontinence
[74]. Therefore, its encoded protein
GABA transporter 1 may be inhibited
by the 33-mer in these patients.
Shared manifestations suggest that
GRINA and PUF60 are altered in CD
and Verheij syndrome
A minority of CD patients suffer other rare
syndromes such as Verheij syndrome,
Kabuki syndrome [117] or Charge syn-
drome, and even more frequently they
share some of their manifestations like
clubfoot, coloboma, atresia [118], heart
defects, hearing loss, cleft palate, devel-
opmental delay, intellectual disability,
short stature, skeletal abnormalities, or
dental problems. Curiously, the splicing
factor PUF60 has been associated with
Verheij syndrome [74]. PUF60 is located
on the 8q24.3 chromosome, the same as
GRINA. A deletion of 8q24 has been
reported in Verheij syndrome [119], while
duplication or triplication of 8p22–8p23
have been found in patients with Kabuki
syndrome [120]. This supports the notion
that common genes are altered in CD and
these syndromes. Hence the screening of
CD and NCGS during pregnancy, along
with a gluten-free diet, should be encour-
aged in order to prevent them.
AMN and HSP90AA1 are involved in
cardiac anomalies
AMN is located on chromosome 14q32.32
and it is involved in the production of
trunk mesoderm (from where cardiac
cells are derived) during development.
Also, HSP90AA1 is located on chromo-
some 14q32.31, and is one of the most
abundant proteins in cardiac cells. Re-
cently, a duplicationon chromosome14q
in a case withmultiple cardiac anomalies
and clubfoot was identified [121]. This
suggests thepossibilitythat deregulation
of these two genes may be involved in
cardiac anomalies in CD patients.
Hypertrophic cardiomyopathy may be
caused by SLC25A3 inhibition
Hypertrophic cardiomyopathy can be
caused by SLC25A3 deficiency [122], but
also by diabetes and thyroid disease,
whicharerespectively2–10and2–4times
more prevalent among CD patients than
the general population [15].
Topiramate side effects
resemble some of the
extradigestive manifestations in
CD and NCGS
Topiramate is used against epilepsy. Its
mechanism of action is not fully under-
stood, but it seems to increase the
activity of some GABA receptors and
antagonize other glutamate receptors,
including GRINA [34], though not
specifically.
Therefore, at least some of the dose-
dependent side effects should mimic the
effects of 33-mer interfering with GRINA
and its interactome. Curiously, some of
these side effects include ataxia, numb-
ness and tingling, continuous eye move-
ments, memory problems, depression,
hearing loss, skin rash, and alopecia,
among others which are somewhat
common in CD and NCGS patients. In
addition, taking topiramate during preg-
nancy may increase the risk of oral
clefts [123], which reinforces the concept
that biochemical inhibition, instead of or
in addition to autoimmunity, may trigger
several of the extradigestive manifesta-
tions observed in CD and NCGS.
Potential for GRINA in
generating novel animal models
In Fig. 1 we illustrate that animal models
of spontaneous CD and NCGS [124], such
as Rhesus macaques, horses, and Irish
Setters (and probably all dogs) share a
longer homologous GRINA region with a
higher number of repetitive domains
in contrast to mice, which show more
deletions and need gliadin sensitization,
chemical treatment, or genetic manipu-
lation in order to manifest symptoms of
CD. Consequently, we speculate that
other animals with fewer deletions than
murine GRINA within the homology
region, e.g., other rodents (Guinea pigs,
degus, and chinchillas), rabbits, cats, or
maybe sheep, may prove superior spon-
taneous models for CD and offer useful
mechanistic information; though in the
case of sheep it would have to be verified
thattheirruminant digestive systemdoes
not lead to complete degradation of the
33-mergliadinfragment.Surprisingly,no
involvement of MHC II alleles has been
found in the dog model, and this remains
to be investigated in horse and mon-
keys [124], reinforcing the suspicion that
additional mechanisms, other than im-
munogenetic ones, may exist in CD.
Future directions
Experiments proposed to verify our
hypothesis are shown in Box 1. For
our model to be true, the 33-mer has to
enter the target extraintestinal cells and
.....Insights & Perspectives A. Garcia-Quintanilla and D. Miranzo-Navarro
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10. interact with the N-terminal domain
of GRINA and its binding partners in
the cytoplasm. Therefore, to verify our
hypothesis it is absolutely necessary to
demonstrate the presence and interac-
tion of the 33-mer with GRINA and
the targets described here, first in cell
cultures and then in vivo, using avail-
able technologies such as microscopy,
co-immunoprecipitation, or proximity
ligation assays. It is also possible that
other prolamin peptide fragments may
contribute to additional symptoms by
interfering with different targets. How-
ever, the ultimate question about what
makes some patients develop certain
symptoms and not others remains open,
hence reflecting the complexity of the
problem. According to us, there must be
factors (yet to be discovered) present
in some individuals, but not in others,
that favor the intracellular entry in such
patients, thus triggering the reported
manifestations. These extradigestive
effects should be reproducible, at least
in part, in immunodeficient animal
models, in order to rule out the
contribution of the immunologic com-
ponent of the disease. Also, the design
and experimental use of 33-mer pep-
tides with mutated residues that prevent
their interaction with GRINA but not the
immunological properties of the pep-
tide, and vice versa, may be useful to
analyze the biochemical and immuno-
logical component of CD. Maybe dea-
midation of Q residues has a role in this,
increasing autoimmune reactions but
decreasing biochemical interactions.
Lastly, further research on the interact-
ing targets is also needed in order to
confirm whether the variants and ex-
pression of these genes are altered in
larger human cohorts of CD and NCGS
with extradigestive manifestations.
Conclusions and outlook
We have shown how the homology
among the 33-mer fragment and GRINA
may enable the 33-mer to interact with
GRINA and its binding partners, and
how the inhibition of these targets
provokes phenotypes that are found in
extraintestinal manifestations of CD
patients, further suggesting their inhi-
bition by the 33-mer.
This hypothesis has several impli-
cations. First, it foresees new animal
models and uncovers potential limita-
tions of current models – i.e., the fact
that they lack most of the homology
with GRINA. Second, it provides a
unifying mechanistic link for many
extradigestive diseases associated with
CD and NCGS, diseases that would
otherwise be isolated and random,
and that are insufficiently explained
by the current immunogenetic model.
Third, it predicts new associations not
yet described in the literature. Fourth, it
may allow the development of new
strategies for specific treatments. And
fifth, it may foster renewed research
interest in CD and NCGS.
Acknowledgments
We thank Sarah K. Garcia-Quintanilla
and Lourdes Garcia-Quintanilla for crit-
ical reading and useful advice.
The authors have declared no conflicts
of interest.
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Box 1
Proposed experiments to verify the hypothesis
Determine if the 33-mer enters inside the target cells.
Verify if the 33-mer interacts with GRINA.
Define who binds the 33-mer in cell extracts from target cells.
Find new binding partners of GRINA.
Explore other animals as spontaneous models of CD and NCGS.
Use immunodeficient animals to discard the immunological component of
the disease.
Design and analyze 33-mer peptide mutants with antigenicity but with
weak or no homology to GRINA (as negative controls).
Reproduce the results using a 33-mer sequence derived from GRINA
(100% homology, but not antigenicity) as a positive control.
Use interfering RNAs and drugs to inhibit GRINA and its interactome and
analyze their effects.
Analyze if the expression of the GRINA interactome is altered in CD and
NCGS patients with extraintestinal manifestations.
A. Garcia-Quintanilla and D. Miranzo-Navarro Insights Perspectives.....
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20. Ferretti A, Parisi P, Villa MP. 2013. The role
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