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R E V I EW
TRAPPopathies: An emerging set of disorders linked tovariations in the genes encoding transport protein particle(TRAPP)-associated proteins
Michael Sacher1,2 | Nassim Shahrzad3 | Hiba Kamel1 | Miroslav P. Milev1
Dsl1 Endoplasmic reticulum (ER) Golgi-to-ER traffic,maintenance of Golgimorphology
Aoki et al130; Sun et al131;Arasaki et al132
May have a role in ER-to-Golgitraffic132,133; functions ofindividual proteins of thecomplex are varied134
COG Cis and medial Golgi, tips andrims of Golgi cisternae, cisand trans Golgi networks,COPI vesicles
Maintenance of Golgimorphology, Golgiretrograde trafficking,tethering of COP I vesiclesto the Golgi, effector ofRab1A and Rab30
Suvorova et al135; Ungaret al127; Oka et al136; Zolovand Lupashin137; Vasileet al138; Miller et al139
Function in retrogradetransport is inferred throughthe subunit-mutantphenotypes (eg,glycosylation failures,vesicle accumulation) andinteraction with proteins(eg, COPI)
TRAPP II Early Golgi, COP I-coatedvesicles, lipid droplets,centrosomal vesicles
COPI vesicle tethering to theearly Golgi; Rab1 and Rab18GEF, intra-Golgi traffic, lipiddroplet homeostasis,ciliogenesis
Yamasaki et al27; Westlakeet al69; Li et al28
Yu et al140 demonstrate a rolefor TRAPPC3 in homotypicCOP II vesicle fusion but itis unclear if the protein isfunctioning outside ofTRAPP nor which TRAPPcomplex is implicated;centrosome localization isdependent upon serumstarvation
TRAPP III Early Golgi, ER exit sites,tubulated recyclingendosomes
ER-to-Golgi traffic, COP IIrecruitment to ER,autophagy
Scrivens et al17; Lamb et al122;Zhao et al19
Tubulated recyclingendosomes were producedby TBC1D14overexpression
CORVET Rab5-positive earlyendosomes
Early endosome tethering andfusion
Perini et al141; van der Kantet al142
HOPS Late endosomes/lysosomes,autophagosomes
Late endosome-lysosomefusion, Rab5-to-Rab7conversion on endosomes,autophagosome-lysosomefusion
Kim et al143; Rink et al144;Jiang et al145; van der Kantet al142
Mammalian HOPS is recruitedto Rab7 positivemembranes by RILP
CHEVI Recycling endosomes, lateendosomes
Endosome recycling to apicalmembranes, lateendosome-lysosome fusion
Smith et al146; van der Kantet al142; Galmes et al147
Localization to late endosomesis seen when co-expressedwith RILP
Schindler et al159 Predominant localization wasto Rab4A-positiveendosomes; also shown tofunction in sorting todense-core vesicles inCaenorhabditis elegans160
Due to space limitations, this table is not to be considered an exhaustive list, but rather a general summary. Comprehensive reviews are available for mostof these complexes.
2 SACHER ET AL.
in TRAPP II, and one additional subunit (Trs85) in TRAPP III.16 All of
the yeast subunits are conserved in higher eukaryotes including
humans (Table 2), while humans and other metazoa contain additional
associated proteins for which no Saccharomyces cerevisiae homologue
has been identified.17 Curiously, a TRAPP I-equivalent complex is yet
to be reported in humans, although human TRAPP II and III complexes
have been described.18,19 The human complexes contain a similar core
of proteins (TRAPPC1, TRAPPC2, two copies of TRAPPC3, TRAPPC4,
TRAPPC5 and TRAPPC6). In addition to this core, TRAPP II also con-
tains TRAPPC9 and TRAPPC10, while TRAPP III contains the core
with TRAPPC8, TRAPPC11, TRAPPC12 and TRAPPC13 (Figure 1B).
Several studies have implicated the TRAPP complexes in the teth-
ering process.15,20,21 It is noteworthy that their role as bona fide
tethers has yet to be definitively demonstrated because these studies
relied largely on crude biochemical fractions, genetics and microcopy
phenotypes. Indeed, their contribution to this process awaits studies
with purified proteins and membranes, and TRAPP complexes may
yet be revealed to function indirectly in this process. As yeast TRAPP
complexes were shown to bind to the small GTPase Ypt1p in its
nucleotide-free state,22 it was speculated that TRAPP could act as a
guanine nucleotide exchange factor (GEF) for this GTPase, converting
it to its active form. Indeed, all three TRAPP complexes have been
reported to have GEF activity toward Ypt1p,14,22,23 and more recently
the TRAPP II complex was shown to have robust GEF activity toward
Ypt31 and the related GTPase Ypt32.24 The GEF activity of recombi-
nant TRAPP I was shown to be dependent upon all of the core pro-
teins except for Trs33 and Trs20.25 A subsequent study revealed the
mechanism for this activity and the key role that the carboxy-terminus
of Bet3 plays in destabilizing the GDP nucleotide bound to the
GTPase.26 Consistent with one study in yeast that demonstrated Ypt1
GEF activity for TRAPP II,26 Yamasaki et al27 demonstrated that the
human TRAPP II complex had GEF activity toward the human Ypt1
homologue called Rab1 but did not report any TRAPP-dependent GEF
activity toward the human homologue of Ypt31 or Ypt32 called
Rab11. In addition, GEF activity of human TRAPP II toward Rab18 has
also been reported.28 It remains unclear as to what, if any, GEF activ-
ity the human TRAPP III complex displays. A recent study focused on
the Drosophila TRAPP complexes demonstrated GEF activity toward
Rab1 and Rab11 but not for Rab18.29
Work predominantly using the yeast model system has suggested
that TRAPP I binds to partially uncoated, ER-derived transport vesi-
cles, and this interaction is mediated by the COP II protein Sec23.20
Subsequent phosphorylation of Sec23 by the Golgi-localized kinase
Hrr25 (casein kinase 1δ in humans) releases TRAPP I from the vesicle
allowing fusion to proceed, a process that is conserved in humans.30
In spite of the elegant work performed on yeast TRAPP I, biochemical
studies on the yeast Trs23 protein raised the possibility that TRAPP I
is an in vitro artifact and may not exist in living cells,31 a notion that
was recently supported by cell biological studies.32 This is consistent
with the lack of identification of a mammalian TRAPP I equivalent and
the inability to express recombinant human TRAPP I, while expression
of recombinant yeast TRAPP I has been accomplished.25 Recent evi-
dence suggests that yeast TRAPP III can fulfill the functions of
TRAPP I.32
FIGURE 1 The yeast and human TRAPP complexes. Cartoons of the
three yeast complexes (A) and the two known mammalian complexes(B) are shown. The core of proteins found in all complexes is coloredin cyan. The arrangement of the subunits within this core is based onits known organization.25,26 The placement of Trs85 in yeast TRAPPIII is based on biochemical and single-particle electron microscopicdata.14,41 The placement of Trs130 and Trs120 is based on genetic,mutational and yeast two-hybrid data.34,36,57,236 It should be notedthat the single-particle electron microscopic data suggests theopposite arrangement,37 a discrepancy that still needs to be resolved.
In the mammalian cartoons, the placement of TRAPPC8 is based onthe homology to the yeast protein as well as one study indicating thatit interacts with TRAPPC2.43 The placement of TRAPPC10 is basedon a study65 that suggests it interacts with TRAPPC2L, and theplacement of TRAPPC9 is based on a biochemical study43
TABLE 2 Conservation of yeast and human TRAPP proteins
Yeast protein Human protein Percent identity/similarity
Bet5 TRAPPC1 33/54
Trs20 TRAPPC2 34/52
Tca17 TRAPPC2L 24/43
Bet3 TRAPPC3, C3L 56/76, 51/73
Trs23 TRAPPC4 29/44
Trs31 TRAPPC5 31/52
Trs33 TRAPPC6A,B 35/51, 33/47
Trs65a
Trs85 TRAPPC8 28/49
Trs120 TRAPPC9 25/44
Trs130 TRAPPC10 24/45
TRAPPC11 —
TRAPPC12 —
TRAPPC13
a Kluyveromyces lactis and Candida glabrata homologues share homology(31% identity/45% similarity) over a relatively small region withTRAPPC13 as revealed by PSI-BLAST.34
SACHER ET AL. 3
In yeast TRAPP II, variants in trs130 were implicated in antero-
grade traffic through or from the Golgi while variants in trs120 only
affected traffic between endosomes and the Golgi,15,33 suggesting dif-
ferent functions for the encoded proteins within the same complex. A
physical interaction was also reported between TRAPP II and COP I in
both yeast and higher eukaryotes.27,28,33 Although non-essential in
yeast, Trs65 was reported to be required for optimal TRAPP II activity,
organization and assembly.34–37 Curiously, although human TRAPP II
was shown to activate Rab1 that is required for ER-to-Golgi traffic,
depletion of the TRAPP II subunit TRAPPC10 (the human homologue
of Trs130) did not affect this step of the biosynthetic pathway.27
The yeast TRAPP III complex contains a single additional subunit,
Trs85, that associates with the core. While originally thought to form
a complex functionally distinct from that of TRAPP I and localized as a
single punctum on the preautophagosomal structure,14,38,39 several
studies implicated Trs85 in ER-to-Golgi traffic15,40 and, using a
brighter fluorescent tag, the TRAPP III complex was shown to also
localize to the Golgi.32 Thus, yeast TRAPP III likely functions in both
ER-to-Golgi traffic and autophagy. Biochemical and structural studies
have shown that the Trs20 protein and its mammalian homologue
TRAPPC2 are required for the attachment of Trs85 (and its mamma-
lian homologue TRAPPC8) to the complex.41–43 In addition to
TRAPPC8, the human TRAPP III complex also contains proteins called
TRAPPC11 (also called c4orf41) and TRAPPC12 (also called TTC15)
that have no readily identifiable yeast homologues.17 This complex
was shown to function in an early stage of the secretory pathway17
and to recruit part of the COP II vesicle coat that functions in this
pathway.19 Like the yeast TRAPP III complex, the human complex was
also implicated in autophagy44,45 (D. Stanga, Q. Zhao, M. Milev,
D. Saint-Dic, C. Mallebrera and M. Sacher, manuscript in preparation).
3 | TRAPPOPATHIES: DISEASESASSOCIATED WITH VARIANTS IN TRAPPPROTEINS
Although assumed to act as a single unit, variations in proteins of the
TRAPP complexes result in distinct disorders with overlapping pheno-
types, suggesting that either portions of the complexes have separate
functions or TRAPP proteins have functions outside of the complex
that are specific to each protein. Indeed, for a number of the TRAPP
proteins linked to human health, the latter appears to be the case. The
following sections will detail disorders linked to known variants in
TRAPP-associated proteins that we now refer to collectively as
TRAPPopathies, and how these variants may result in the distinct phe-
notypes reported. We briefly discuss what is known about each pro-
tein and its structure, and then discuss clinical phenotypes, attempting
to relate them to either a TRAPP or a non-TRAPP function. A sum-
mary of all known TRAPP gene variants to date, the resulting protein
variants and their associated phenotypes is presented in Table 3, eas-
ily allowing the readers to map the variant to the protein or a domain
within the affected protein. Readers are directed to several earlier
reviews touching upon some aspects of TRAPP proteins in disease in
a more concise manner.16,46
3.1 | TRAPPC2 (MIM 300202)
The yeast Trs20 protein was identified as a component of TRAPP in
the initial report of the yeast TRAPP complex.13 This protein, display-
ing 34% identity and 54% similarity with human TRAPPC2 (Table 2),
was found in substoichiometric amounts in the yeast TRAPP I com-
plex, and was subsequently shown to be required for the stable
attachment of the yeast protein Trs85 to the TRAPP III complex.41,42
The human protein, going by the names sedlin, SEDL, TRAPPC2 and
hTrs20, can functionally replace its yeast homologue,47 suggesting an
evolutionarily conserved function for the protein. Consistent with its
conserved function, TRAPPC2 was shown to be required for the asso-
ciation of both TRAPPC8 and TRAPPC9 with the human TRAPP
complex.43
The crystal structure of TRAPPC2 was solved and shown to
resemble that of the amino-terminal regulatory domain of the SNARE
proteins Sec22 and Ykt6.48 This similarity led to the suggestion that
TRAPPC2 either regulated the function of SNARE proteins and/or
acted as a protein adaptor, both of which have been supported by
subsequent studies in yeast and higher eukaryotes.41–43 The overall
fold of TRAPPC2 and the regulatory domain of these SNARE proteins
have been referred to as longin-domain folds which are found in many
trafficking proteins.49 Interestingly, several other TRAPP core proteins
also adopt a three-dimensional structure similar to that of
TRAPPC2.25 A study that elucidated the architecture of the core pro-
teins of TRAPP (TRAPPC1, TRAPPC2, TRAPPC3, TRAPPC4, TRAPPC5
and TRAPPC6) suggested that one surface of TRAPPC2 was involved
in interactions with TRAPPC5, but the remainder of the protein was
well-suited to mediate other interactions,25 consistent with its pro-
posed role as a TRAPP protein adaptor.
In addition to its function in membrane trafficking by association
with the TRAPP complex, TRAPPC2 was identified as a protein called
MIP-2a that regulates the activity of the transcriptional repressor pro-
tein MBP-1.50 MIP-2a appears to arise from transcription of what was
thought to be a TRAPPC2 pseudogene on chromosome 19.51 The
expression of MIP-2a differs from that of TRAPPC252 although the
functional significance of this is unclear as the two proteins are identi-
cal. A more recent study found that MIP-2a was a target of the anili-
noquinazoline Q15, a compound that induces apoptosis.53 Q15
disrupted the interaction between MIP-2a and MBP-1 leading to an
accumulation of the latter in the nucleus that resulted in an inhibition
of c-myc transcription and, ultimately, cell death.
In 2012, Venditti et al presented an elegant model for the role of
TRAPPC2 in the regulation of the export of collagen from the ER.54
Emergence of a vesicle at the ER is dependent upon the activity of
the GTPase Sar1.55 TRAPPC2 enhances the inactivation of Sar1 at ER
exit sites,54 thereby preventing membrane constriction and allowing
nascent vesicles to grow to a size sufficient to accommodate the large
procollagen fibrils. Interestingly, TRAPPC2 is recruited specifically to
the sites of procollagen export via an interaction with the procollagen
receptor TANGO1.
Although its inclusion as a TRAPP component was originally
inferred by analogy to its yeast homologue Trs20, TRAPPC2 was
shown to be present in a high-molecular-weight fraction of a size
exclusion column.56 Subsequent studies showed that the protein
4 SACHER ET AL.
TABLE
3Variantsin
TRAPPge
nes
Subu
nit,MIM
forprotein
DNAva
rian
t(rep
orted
)Predicted
/rep
orted
protein
chan
gePhe
notype
ordiso
rder
MIM
for
diso
rder
Referen
ceNotes
TRAPPC2
MIM
:300202
c.139G>T
p.Asp47Tyr
SEDT
313400
Ged
eonet
al59
c.218C>T
p.Se
r73Le
uSE
DT
313400
Shaw
etal61;G
edeo
net
al59;
Zho
uet
al62
Oneindividualalso
has
Leber
hered
itaryopticneu
ropathydue
toamtD
NAmutation
c.239A>G
p.His80Arg
SEDT
313400
Linet
al161
c.248T>C
p.Phe
83Se
rSE
DT
313400
Grune
baum
etal60
c.389T>A
p.Val130Asp
SEDT
313400
Ged
eonet
al59
c.53-54de
lTT
p.Phe
18*
SEDT
313400
Ged
eonet
al58,59
c.61G>T
p.Glu21*
SEDT
313400
Xiaet
al162
c.167C>A
p.Se
r56*
SEDT
313400
Fiedler
etal163
c.182T>A
p.Le
u61*
SEDT
313400
Ged
eonet
al59
c.210G>A
p.Trp70*
SEDT
313400
Christieet
al164
c.210G>Aan
dc.325de
lTp.Trp70*an
dp.
Ser110Glnfs*2
SEDT
313400
Fiedler
etal165
Oneoftw
oindividualswithtw
oseparatevarian
tsin
thege
ne
c.209G>A
p.Trp70*
SEDT
313400
Zhu
etal166;C
aoet
al167
c.271C>T
p.Gln91*
SEDT
313400
Ged
eonet
al59
c.329C>A
p.Se
r110*
SEDT
313400
Shie
tal168
c.345_3
46de
lTG
p.Tyr115*
SEDT
313400
Fiedler
etal165
c.364C>T
p.Arg122*
SEDT
313400
Christieet
al164
c.391C>T
p.Gln131*
SEDT
313400
Takah
ashi
etal169
c.6de
lp.Se
r4Alafs*5
SEDT
313400
Gomes
etal170
Individualisdouble
heterozygo
us
forTR
APPC2an
dFG
FR3
c.1138G>Awithaco
mpound
phen
otypeofachondrodysplasia
andSE
DT
c.94-2A>G
p.Asp32Ile
fs*2
SEDT
313400
Fuk
umaet
al171
Predictedsplicevarian
tin
the
intronupstream
ofex
on4;
predictedto
resultin
skippingof
exon4
c.99de
lCan
dc.236-5_8
delATTA
p.His34Ile
fs*4
SEDT
313400
Fiedler
etal165
Oneoftw
oindividualswithtw
oseparatevarian
tsin
thege
ne;
the
intronicdeletionispredictedto
resultin
thedeletionofex
on5
c.157_1
58de
lAT
p.Met53Asnfs*3
5SE
DT
313400
Ged
eonet
al58,59;F
iedleret
al165
c.183_1
84de
lGA
p.Ly
s62Asnfs*2
6SE
DT
313400
Fiedler
etal165
c.191_1
92de
lTG
p.Val64Glyfs*2
4SE
DT
313400
Ged
eonet
al58,59
c.197_3
24+121de
l693
ND
SEDT
313400
Takagie
tal172
693bpdeletionstartingin
exon
4an
den
dingin
intron
5follo
wingthefifthex
on (Con
tinu
es)
SACHER ET AL. 5
TABLE
3(Continue
d)
Subu
nit,MIM
forprotein
DNAva
rian
t(rep
orted
)Predicted
/rep
orted
protein
chan
gePhe
notype
ordiso
rder
MIM
for
diso
rder
Referen
ceNotes
c.239-9_1
2de
lTTAA
ND
SEDT
313400
Ged
eonet
al59;F
iedleret
al165
Predictedsplicevarian
tin
the
intronupstream
ofex
on
5(IV
S4-9_1
2delTTAA)
c.239-4_1
1de
lAATTATTT
ND
SEDT
313400
Ged
eonet
al59
Predictedsplicevarian
tin
the
intronupstream
ofex
on
5(IV
S4-4_1
1delAATTATTT)
c.241_2
42de
lAT
p.Met81Glufs*7
SEDT
313400
Mum
met
al173;G
edeo
net
al59
c.262_2
66de
lGACAT
p.Asp88Ly
sfs*12
SEDT
313400
Ged
eonet
al59
c.267_2
71de
lAAGAC
p.Gln91Argfs*9
SEDT
313400
Mum
met
al174;S
huet
al175;F
iedler
etal176;L
ietal177
c.271_2
75de
lCAAGA
p.Gln91Argfs*9
SEDT
313400
Ged
eonet
al59;F
iedleret
al165
c.272_2
73de
lAA
p.Gln91Argfs*1
0SE
DT
313400
Ged
eonet
al59
c.293de
lTp.Phe
98Se
rfs*10
SEDT
313400
Xiaoet
al178
c.325-4_1
0de
lTCTTTCCinsA
A)
ND
SEDT
313400
Ged
eonet
al59;F
iedleret
al165
Predictedsplicevarian
tin
the
intronupstream
ofex
on
6(IV
S5-4_1
0delTCTTTCCinsA
A)
c.333_3
36de
lGAAT
p.Met111Ile
fs*2
8SE
DT
313400
Shaw
etal179
c.341-11_9
delAAT
ND
SEDT
313400
Daviset
al180
Splicevarian
tthat
resultsin
the
deletionofex
on5
c.384de
lAp.Val130Phe
fs*1
0SE
DT
313400
Bar-Yosefet
al181
Exo
n3de
letion
Absen
tSE
DT
313400
Matsuie
tal182
1763bpdeletionen
compassing
partofex
on3harboringthe
initiatormethioninean
dthe
precedingintron
Exo
n3de
letion
Absen
tSE
DT
313400
Ged
eonet
al59
Thedeletionen
compassesex
on
3harboringtheinitiator
methionine
Exo
n3de
letion
Absen
tSE
DT
313400
Fiedler
etal165
Anunmap
ped
deletion
enco
mpassingex
on3harboring
theinitiatormethionine
Exo
n4-exo
n6de
letion
ND
SEDT
313400
Fiedler
etal165
Alargeunmap
ped
deletion
enco
mpassingex
ons4-6
Exo
n6de
letion
ND
SEDT
313400
Shaw
etal179;G
edeo
net
al59
1335bpdeletionen
compassing
partofex
on6an
dthepreceding
intron
Exo
n6de
letion
ND
SEDT
313400
Christieet
al164
1445bpan
d750bpdeletions
enco
mpassingpartofex
on6an
dtheprecedingintron
6 SACHER ET AL.
TABLE
3(Continue
d)
Subu
nit,MIM
forprotein
DNAva
rian
t(rep
orted
)Predicted
/rep
orted
protein
chan
gePhe
notype
ordiso
rder
MIM
for
diso
rder
Referen
ceNotes
c.322-1_2
delAG
c.322_3
32de
lTTTCAATGAA
p.Asp109_Ser123de
l,Se
r124fs*2
SEDT
313400
Luet
al183;M
aet
al184
13bpdeletionspan
ningthefirst
11bpofex
on6an
dthelast
twobases
ofthepreceding
intronresultingin
theactivation
ofacryp
ticsplicesite
inex
on6;
based
onNM_0
01011658.3
varian
tisp.Phe1
09_Ser123del,
Ser124Cysfs*3
c.-21A>G
ND
SEDT
313400
Ged
eonet
al59;R
uyanie
tal185
Predictedsplicevarian
tin
the
intronupstream
ofex
on
3harboringthefirstco
dingex
on
(IVS2
-2A>G)
c.-21A>C
ND
SEDT
313400
Gao
etal186;L
uoet
al187
Predictedsplicevarian
tin
the
intronupstream
ofex
on3,the
firstco
dingex
on(IV
S2-2A>C)
c.93+1G>A
p.Asp32Ile
fs*2
1SE
DT
313400
Ada
chie
tal188
Splicevarian
tresultingin
the
insertionofATACbetwee
nex
on
3an
dex
on4
c.93+5G>A
Absen
tSE
DT
313400
Ged
eonet
al59;T
iller
etal189;
Fiedler
etal165;R
yuet
al190;
Wan
get
al191;W
uet
al192
Predictedsplicevarian
tpredicted
todeleteex
on3harboringthe
initiatormethionine
(IVS3
+5G>A)
c.237+1A>G
p.His80Profs*1
4SE
DT
313400
Guo
etal193;X
ionget
al194
Splicevarian
tthat
resultsin
the
deletionofthefirstfive
bases
of
exon5(IV
S4+1A>G)
c.237+4T>C
p.His80Thrfs*1
1SE
DT
313400
Shaw
etal179
Splicevarian
tthat
resultsin
exon
4follo
wed
by113bpofthe
subsequen
tintron(IV
S4+4T>C)
c.320_3
21insT
p.Phe
109Valfs*8
SEDT
313400
Ged
eonet
al59
c.325-2A>C
ND
SEDT
313400
Ged
eonet
al59
Predictedsplicevarian
tin
the
intronupstream
ofex
on
6(IV
S5-2A>C)
c.370_3
71insA
p.Se
r124Ly
sfs*4
SEDT
313400
Xiaet
al195
TRAPPC2L
MIM
:610970
c.33+1G>A
c.294+6_9
delTCAG
p.Val69_Ser98de
l;full-leng
thprotein
also
detected
Mild
tomode
rate
deve
lopm
ental
delaywithsomeworsen
ing
follo
wingacuteillne
ss
—P.van
Hasselt(personal
commun
ication)
Compoundheterozygo
us;thefirst
varian
tispredictedto
resultin
deletionofex
on1harboringthe
initiatormethionine,
theseco
nd
resultsin
exon3deletionan
dan
in-framedeletionof30am
ino
acids;inco
mplete
pen
etrance
since
full-lengthwild
-typ
eprotein
isalso
detected
c.109G>T
p.Asp37Tyr
Neu
rode
velopm
entald
elay,feb
rile
illne
ss-ind
uced
enceph
alopa
thy,
—Milevet
al65
(Con
tinu
es)
SACHER ET AL. 7
TABLE
3(Continue
d)
Subu
nit,MIM
forprotein
DNAva
rian
t(rep
orted
)Predicted
/rep
orted
protein
chan
gePhe
notype
ordiso
rder
MIM
for
diso
rder
Referen
ceNotes
rhab
domyo
lysis,de
velopm
ental
arrest,e
pilepsy,tetrap
legia
TRAPPC6A
MIM
:610396
Naturalvarian
tp.Val29_Lys42de
lFoun
din
brainplaq
uesin
norm
alan
dAlzhe
imer'sdiseasepa
tien
ts—
Cha
nget
al71
Naturally
occurringsplicevarian
tthat
lead
sto
inan
in-frame
deletionof14am
inoacids
(TRAPPC6A1orTRAPPC6Δ)
c.319T>A
p.Tyr107Asn
Intellectua
ldisab
ility,spe
echde
lay,
facialdy
smorphism
,polyda
ctyly
Moha
moud
etal78
Oneoffive
rare,h
omozygo
us,
predictedpathoge
nicvarian
tsthat
includevarian
tsin
ANKK1,
RPSH
6A,A
LKBH8an
dAMOTL
1
TRAPPC6B
MIM
:610397
c.82-2A>G
p.Glu28Valfs*1
1Microceph
aly,
epilepsy,au
tistic
features,gen
eralized
wea
kness,
ataxicgait,corticalatroph
y,thin
corpus
callo
sum
—Marin-V
alen
ciaet
al82
Splicevarian
tthat
deletes
exon2
c.124C>T
p.Arg42*
Non-synd
romicau
tosomal
recessiveintellectua
ldisab
ility
(NS-ARID
)
—Harripa
ulet
al81
c.485G>A
p.Arg50Se
rfs*2
Restlesslegs
synd
rome2(RLS
2)
608831
Arido
net
al83
Variantresultsin
exon3skipping,
predictedprotein
isforex
on
2-exo
n4varian
t;au
tosomal
dominan
tinheritan
ce;o
riginal
mutationtake
sinto
acco
untthe
first335bpofuntran
slated
regionan
dtheaffected
baseisc.
G150
TRAPPC9
MIM
:611966
c.1423C>T
p.Arg475*
Seve
reintellectua
ldisab
ility,
microceph
aly,diminishe
dwhite
mattervo
lume,
thinning
ofthe
corpus
callo
sum,red
uced
cerebe
llarvo
lume
613192
Miret
al196;A
bouJamra
etal197;
Moch
idaet
al198;G
iorgio
etal199;
Abb
asie
tal200;H
arripau
letal81
c.2065G>T
p.Glu689*
Seve
reintellectua
ldisab
ility,
microceph
aly,motorde
lay,
absent
spee
ch,corpus
callo
sum
thinning
,red
uced
white
matter
613192
Abb
asie
tal200
c.2311_2
314de
lTGTT
p.Le
u772Trpfs*7
Mode
rate
toseve
remen
tal
retardation/intellectua
ldisab
ility,
borderlin
emicroceph
alyin
some
individu
als,diminishe
dwhite
mattervo
lume,
thinning
ofthe
corpus
callo
sum
613192
Miret
al196
c.1708C>T
p.Arg570*
Men
talretarda
tion,
microceph
aly,
mye
linations
defects
613192
Philip
peet
al201;M
ortreuxet
al202
c.2851-2A>C
p.Thr951Tyrfs*1
7Hyp
otonia,intellectua
ldisab
ility,
diminishe
dwhite
mattervo
lume,
thinning
oftheco
rpus
callo
sum,
613192
Maran
giet
al203
Splicevarian
tthat
resultsin
deletionofex
on18
8 SACHER ET AL.
TABLE
3(Continue
d)
Subu
nit,MIM
forprotein
DNAva
rian
t(rep
orted
)Predicted
/rep
orted
protein
chan
gePhe
notype
ordiso
rder
MIM
for
diso
rder
Referen
ceNotes
head
circum
ferenc
ebe
twee
n2nd
and10th
centile
c.1024+1G>T
p.Arg293Se
rfs*36
p.His294Glyfs*7
Intellectua
ldisab
ility,m
icroceph
aly
613192
Kakar
etal204;A
bbasie
tal200
Splicevarian
tthat
resultsin
deletionofex
on3an
dboth
exons3an
d4
c.1532C>T
p.Thr511Met
Norm
osm
ichy
pogo
nado
tropic
hypo
gona
dism
(nHH)a
ndKallm
annsynd
rome(KS)
613192
Qua
ynoret
al94
InNM_0
31466.7
varian
tis
c.1826C>Tresultingin
p.
Thr609Met;b
igen
icvarian
tthat
co-seg
regateswithPDE3A
c.1477G>A
c.568_5
74de
lTGGCCAC
Exo
n9-16du
plication
p.Trp190Argfs*9
5ND
Thinco
rpus
callo
sum,sev
ere
intellectua
ldisab
ility,w
hite
matterab
norm
alities,dy
smorphic
features
(includ
inghy
pertelorism
,prominen
tna
salb
ridg
e,short
philtrum,large
chee
ks)
613192
Mortreux
etal202
Compoundheterozygo
uswiththe
seco
ndallele
harboringan
in-frameduplicationofex
ons
9-16
c.2134C>T
Exo
n18-19de
letion
p.Arg712*
ND
Microceph
aly,
thin
corpus
callo
sum,
seve
reintellectua
ldisab
ility,
dysm
orphicfeatures
(includ
ing
shortph
iltrum,large
chee
ks)
613192
Mortreux
etal202
Compoundheterozygo
uswiththe
seco
ndallele
harboringan
out-of-fram
edeletionofex
ons
18-19
Exo
n2-9
duplication
ND
Microceph
aly,
thin
corpus
callo
sum,
seve
reintellectua
ldisab
ility,
dysm
orphicfeatures
(includ
ing
shortph
iltrum,large
chee
ks)
613192
Mortreux
etal202
Homozygo
usduplicationofex
ons
2-9
aswellasa61bpinsertion
resultingin
anout-of-fram
epolypep
tide
c.533T>C
p.Le
u178Pro
Cong
enitalmicroceph
aly,seve
reintellectua
ldisab
ility,
hype
rkinesia,h
ypoplasia
ofthe
corpus
callo
sum,m
ildco
lpoceph
aly,
epilepsy
613192
Due
rinc
kxet
al205
Affectedsiblin
gsalso
havea
truncatingp.Arg741*nonsense
varian
tin
theMCPH1,alsofound
inanon-affectedsiblin
g
TRAPPC11
MIM
:614138
c.2938G>A
p.Gly980Arg
LGMD2S,
elev
ated
CK,sco
liosis,
cataracts
615356
Böge
rsha
usen
etal107
c.1287+5G>A
p.Ala372_Ser429de
lMyo
pathy,elev
ated
CK,e
pilepsy,
deve
lopm
entald
elay,ataxia,
cerebralatroph
y,microceph
aly
615356
Böge
rsha
usen
etal107
Splicevarian
tthat
deletes
exon
12resultingin
anin-frame
deletionin
conjunctionwitha
naturally-occurringskippingof
exon11
c.661-1G>T
c.2938G>A
p.Le
u240Alafs*1
0p.Le
u240Valfs*7
p.Gly980Arg
Slightly
redu
cedwhite
matter
volume,
cataracts,elev
ated
CK,
hepa
tomeg
aly,
elev
ated
AST
and
ALT
,steatohe
patitis,co
ngen
ital
muscu
lardy
stroph
y,lordosis
615356
Lian
get
al108
Compoundheterozygo
us;the
intronicvarian
tresultsin
two
splicingvarian
ts
c.1141C>G
c.3310A>G
p.Pro381Ala
p.Thr1104Ala
Hyp
otonia,seizures,m
icroceph
aly,
camptoda
ctyly,
cholestasis,
—Matalong
aet
al112
Compoundheterozygo
us
(Con
tinu
es)
SACHER ET AL. 9
TABLE
3(Continue
d)
Subu
nit,MIM
forprotein
DNAva
rian
t(rep
orted
)Predicted
/rep
orted
protein
chan
gePhe
notype
ordiso
rder
MIM
for
diso
rder
Referen
ceNotes
neph
ropa
thy,
osteo
pathy,N-an
dO-glyco
sylationde
fects(CDG)
c.1893+3A>G
p.Val588Glyfs*1
6Alacrim
a,acha
lasia,scolio
sis,
cerebralatroph
y,myo
pathy,
intellectua
ldisab
ility,gait
abno
rmalities,shortstature
615356
Koeh
leret
al109
Splicevarian
tthat
deletes
exon18
c.2330A>C
c.513_5
16de
lTTTG
p.Gln777Pro
p.Phe
173Tyrfs*1
3ElevatedCK,d
ystroph
icch
ange
s,low
α-dy
stroglycan
,elevatedAST
andALT
,liver
fibrosis,mild
cerebralatroph
y
615356
Fee
etal110
Compoundheterozygo
us
c.851A>C
c.965+5G>T
p.Gln284Pro
p.Ile
278_G
ln351de
lCMD,e
levatedCK,
hypo
glycosylationof
α-dy
stroglycan
,cereb
ralatroph
y,de
velopm
entald
elay
615356
Larsonet
al111
Compoundheterozygo
us;splice
varian
tthat
deletes
exon9an
dthefirst88bases
ofex
on
10resultingin
anin-frame
deletion
c.1192C>T
c.3014C>T
p.Arg398*
p.Pro1005Le
uLG
MD,p
rogressive
proximalmuscle
wea
kness,elev
ated
CK,lactate
dehy
droge
nase
and
α-hy
droxybu
tarate
dehy
droge
nase
615356
Wan
get
al113
Compoundheterozygo
us
c.1287+5G>A
c.3379_3
380insT
p.Ala372_Ser429de
lp.Asp1127Valfs*4
7W
eakn
ess,microceph
aly,co
gnitive
impa
irmen
t,elev
ated
CK,
spasticity,cho
reiform
move
men
ts,cereb
ralatroph
y
615356
C.Jim
enez
Mallebrera
(personal
commun
ication)
Compoundheterozygo
us
c.2389C>T
p.Gln797*
ElevatedCK,w
eakn
ess,spasticity,
dystonia,de
velopm
entald
elay
—S.
Edv
ardson(personal
commun
ication)
Presumed
compoundheterozygo
us
buttheseco
ndpresumed
intronicvarian
thas
yetto
be
determined
c.(1756,2938)G>A
c.100C>T
p.Gly980Arg
p.Arg34*
Delayed
motorde
velopm
ent,calf
hype
rtroph
y,cataracts,elev
ated
CK,LGMD,d
ystroph
icch
ange
s
615356
A.M
anzuran
dF.M
untoni(personal
commun
ication)
Compoundheterozygo
us;
c.1756G>Aisasilentmutation
TRAPPC12
MIM
:614139
c.145de
lGp.Glu49Argfs*1
4Trunc
alhy
potonia,microceph
aly,
appe
ndicular
spasticity,
hypsarrythmia,e
pilepsy,po
nshy
poplasia,p
artialagen
esisof
theco
rpus
callo
sum,b
rain
atroph
y
—Milevet
al124
c.360du
pCc.1880C>T
p.Glu121Argfs*7
p.Ala627Val
Pons
hypo
plasia,age
nesisofthe
corpus
callo
sum,b
rain
atroph
y,spasticqu
adripleg
ia,m
yoclonic
jerks,seizures,spa
sticity,
neuroge
nicblad
der
—Milevet
al124
Compoundheterozygo
us
Abb
reviations:A
LT,alanine
aminotran
sferase;
AST
,aspartate
aminotran
sferase;
CDG,cong
enitaldisorder
ofglycosylation;
CK,creatinekina
se;L
GMD,lim
bgirdle
musculardystrophy;
ND,n
otdetermined
.The
referenc
esequ
encesused
were:
NM_0
01011658.3
(TRAPPC2),NM_0
16209.4
(TRAPPC2L),N
M_0
24108.2
(TRAPPC6A),NM_1
77452.3
(TRAPPC6B),NM_0
31466.7
(TRAPPC9),NM_0
21942.5
(TRAPPC11)an
dNM_0
16030.5
(TRAPPC12);allv
ariantsareho
mozygo
usun
less
otherwiseno
ted;
allv
ariantsarerecessiveun
less
otherwiseno
ted;
inmost
cases,varian
tsarelistedas
reported
intheprimaryreference
exceptforvari-
ants
repo
rted
asIVSan
dno
n-HGVSno
men
claturevarian
ts,w
hich
have
been
conv
ertedto
HGVSno
men
clature;
protein
varian
tswereve
rified
usingMutationTaster2
06an
dan
ydiscrep
ancies
withthepublished
pap
erreferto
theMutationT
astervarian
t.
10 SACHER ET AL.
physically interacts directly or indirectly with several core TRAPP pro-
teins including TRAPPC3, TRAPPC4 and TRAPPC5, as well as with
complex-specific proteins including TRAPPC8, TRAPPC9, TRAPPC10,
TRAPPC11 and TRAPPC12.17,25,43,57 Localization studies have
with a marker for early endosomes, suggesting that TRAPP complexes
containing TRAPPC2L may function in a post-Golgi compartment.
Recently, individuals were identified with homozygous variants in
TRAPPC2L.65 Interestingly, the individuals were found to have a mis-
sense variant of the conserved Asp37 residue (p.Asp37Tyr). As stated
above, the identical variant in TRAPPC2 results in the skeletal defect
SEDT. In contrast, the TRAPPC2L individuals harboring this variant
suffer from a global developmental delay, microcephaly, dystonia, tet-
raplegia, rhabdomyolysis, encephalopathy and epilepsy. The p.
Asp37Tyr variant and the equivalent yeast variant (Tca17 Asp45Tyr)
both interfere with the interaction between TRAPPC2L and
TRAPPC10 (Trs130 in yeast). Although a TRAPPC2L knockdown in
HeLa cells results in a fragmentation of the Golgi,57 fibroblasts derived
from the individuals with TRAPPC2L variants did not display an
abnormal Golgi morphology.65 These fibroblasts had defects in the
trafficking of Golgi marker proteins and also displayed a defect in the
exit of a marker protein from the Golgi. Interestingly, GFP-tagged
FIGURE 2 The location of the conserved leucine and aspartic acid
residues on TRAPPC2 and TRAPPC2L. A, TRAPPC2L was modeledusing the structure of its yeast homologue Tca17 (PDB ID: 3PR6). Thehighly similar structure of TRAPPC2 (PDB ID: 1H3Q) is shown on theright for comparison. The location of alpha helix α1, where the onlytwo conserved residues between the two proteins are found, isindicated. B, A close-up view of the overlay of helices α1 fromTRAPPC2L and TRAPPC2 with the conserved leucine and asparticacid residues is shown. The side chains are oriented similarly. Note
that helix α1 is not involved in the interaction between TRAPPC2 andother TRAPP subunits of the core complex. The ribbons are colored asin panel A
SACHER ET AL. 11
Rab11 localization was altered, with larger and/or more abundant
GFP-Rab11 punctae. In addition, there was an increased level of the
active (GTP-bound) form of Rab11. This suggests that TRAPPC2L
either negatively regulates the GEF activity of TRAPP for Rab11, or it
participates in the recruitment of a Rab11 GAP. The recruitment of a
GAP by a TRAPP complex was recently demonstrated in yeast.66 As
Rab11 has been implicated in trafficking at recycling endosomes,67
the earlier finding that TRAPPC2L fractionates with light membranes
that may also contain the endosomal marker EEA1 is consistent with
TRAPPC2L and Rab11 functioning on the same membranes. It is note-
worthy that the yeast TRAPP II complex (that contains the TRAPPC2L
homologue Tca17) was recently demonstrated to facilitate nucleotide
exchange on the yeast Rab11 homologues Ypt31 and Ypt32,24 further
strengthening the connection between TRAPPC2L and Rab11. It
should be noted that a formal demonstration of the involvement of a
human TRAPPC2L-containing TRAPP complex acting as a GEF for
Rab11 has yet to be shown. Given the large number of effector pro-
teins for Rab11,68 it remains to be seen how overactivation of this
GTPase results in the clinical pathology of these individuals. As a
potential clue, a defect in ciliogenesis and cilia length was noted in the
fibroblasts from these individuals, consistent with the link between
TRAPP, Rab11 and cilia.69
3.3 | TRAPPC6A (MIM 610396)
Three isoforms of the TRAPPC6 protein have been described in
humans. These include TRAPPC6A1, TRAPPC6A2 and TRAPPC6B.70
TRAPPC6A1 and TRAPPC6B are encoded by different genes and
share 56% identity and 72% similarity, while TRAPPC6A2 contains an
additional, internal 14 amino acid stretch compared to TRAPPC6A1.
In light of this difference, TRAPPC6A1 has also been referred to in
more recent literature as TRAPPC6AΔ.71,72 In yeast, the TRAPPC6
homologue Trs33 has been implicated in assembly of the TRAPP II
complex via an interaction with the TRAPP II-specific subunit
Trs120.36
TRAPPC6A was implicated in pigmentation in a mosaic hypopig-
mentation (mhyp) mouse in which a provirus randomly inserted into
the intron immediately following exon 1 of the gene.73 The authors
suggested that TRAPPC6A is involved in the biogenesis of melano-
somes. It is noteworthy that the expression of the TRAPPC6A gene
was nearly completely turned off in this mouse. Given that the gene
likely shares a promoter in a head-to-head fashion with its neighbor-
ing gene BLOC1S3 whose product is implicated in melanosome bio-
genesis and hypopigmentation,74 reduced expression of BLOC1S3
would also be expected in the mhyp mouse calling into question the
role of TRAPPC6A in pigmentation.
The crystal structure of TRAPPC6A1 was solved in a heterodi-
meric complex with its TRAPP binding partner TRAPPC3.75 Remark-
ably, although these two proteins share little sequence identity, the
overall folds of the two proteins were strikingly similar with both pro-
teins composed of a mixed α/β-fold containing four α-helices and four
β-strands forming an antiparallel β-sheet. One notable difference
between these proteins is the absence of a hydrophobic tunnel in
TRAPPC6A1 that was seen in the TRAPPC3 crystal structure.76
TRAPPC6A1 was recently found in extracellular plaques from the
brain cortex of individuals with Alzheimer's disease (AD).71 These pla-
ques were also reactive with an antibody that recognizes
Ser35-phosphorylated TRAPPC6A1. Although it is unclear how this
otherwise cytosolic protein would be released from cells, the authors
propose a mechanism for aggregation of TRAPPC6A1. WWOX, a
tumor suppressor, prevents aggregation of TRAPPC6A1. When
WWOX is downregulated, as it is in AD individuals, TRAPPC6A1 is
phosphorylated at Ser35, aggregates and induces caspase 3 activation,
which has been proposed to contribute to the production of the path-
ogenic Aβ peptide.77 TRAPPC6A1 would then serve as a platform for
Aβ plaque formation. A subsequent report demonstrated that zinc
finger-like protein that regulates apoptosis (Zfra), a naturally occurring
31 amino acid peptide, reduced phosphorylation of TRAPPC6A1 and
prevented its deposition in cortical plaques.72 It remains unclear what
role TRAPPC6A1 plays in the etiology of AD. A TRAPPC6A2 missense
variant was recently reported in individuals with a clinical spectrum
including intellectual deficit, speech delay, polydactyly and facial dys-
morphism.78 The variant was one of five homozygous variants
detected in these individuals, all of which are rare and predicted to be
pathogenic. While some of the clinical features are similar to those of
individuals harboring other TRAPP gene variants (see Table 3), it is
unclear if the clinical features in these individuals are due to the
TRAPPC6A2 variant, one of the other variants or some combination
of the five variants.
3.4 | TRAPPC6B (MIM 610397)
The structure of TRAPPC6B was solved both as a homodimer79 and a
heterodimer in a complex with TRAPPC3.80 Not unexpectedly, the
TRAPPC6A1-TRAPPC3 and TRAPPC6B-TRAPPC3 heterodimers are
nearly the same, although the TRAPPC6A1-containing heterodimer
occupies a larger surface area of TRAPPC3 than does the one contain-
ing TRAPPC6B. A small stretch of non-conserved amino acids maps to
the surface of each heterodimer, suggesting that the heterodimers
may interact with different proteins although tissue-specific expres-
sion was not seen for either of the isoforms in mouse tissue.80 Both
heterodimers formed a heterotrimeric complex with TRAPPC1,25,80
suggesting they can interact with other TRAPP proteins to form iso-
complexes. Proof of such isocomplexes was demonstrated by immu-
noprecipitation studies in mammalian cells.70
Variants in TRAPPC6B were recently reported. In one study
aimed at identifying genetic variants contributing to non-syndromic
autosomal recessive intellectual disability (NS-ARID) in 192 consan-
guineous Iranian and Pakistani families, a truncating variant in
TRAPPC6B was reported.81 The same study also identified a truncat-
ing variant in the TRAPP gene encoding TRAPPC9 in another family.
This is of interest given the interaction between the yeast homo-
logues for TRAPPC6 and TRAPPC9 (Trs33 and Trs120, respectively;
see above). A second report identified TRAPPC6B splice variants in six
individuals from three unrelated consanguineous families of Egyptian
origin.82 All affected individuals had similar phenotypes that included
microcephaly, epilepsy and brain malformations including atrophy and
thinning of the corpus callosum. These phenotypes are similar to
those of individuals with TRAPPC9 variants (Table 3) and may result
12 SACHER ET AL.
from an impaired association of TRAPPC9 with TRAPP II. A third
study identified a heterozygous TRAPPC6B variant in an individual
with restless legs syndrome 2.83 Fourteen other variants were
excluded due to either high frequency in the population or mild pre-
dicted effect. The resulting protein (p.Arg50Serfs*2) represents a
severe truncation and is presumed autosomal dominant by the
authors. If TRAPPC6B interacts with TRAPPC9, there might be an
expectation of a TRAPPC9-related phenotype (eg, microcephaly, intel-
lectual disability). However, no such phenotype was reported. This
would suggest that either there are sufficient TRAPPC9-containing
TRAPP complexes remaining or the truncated protein may still inter-
act with TRAPPC9 but not with some other, perhaps non-TRAPP,
protein.
3.5 | TRAPPC9 (MIM 611966)
Following the discovery of Trs120 in yeast as a component of TRAPP
II,13,15 TRAPPC9, its human homologue, was detected in immunopre-
cipitates employing tagged versions of TRAPPC3,70 TRAPPC217,43
and TRAPPC2L,17 as well as in a high-molecular-weight complex.27
TRAPPC9 is thought to be a component of a TRAPPC10-containing
complex.18 However, while TRAPPC9 was implicated in ER-derived
COP II vesicle dynamics,84 TRAPPC10 depletion did not affect this
membrane trafficking step.27 A TRAPPC9-containing complex bound
to Rab18 in its nucleotide-free form and was shown to have GEF
activity for this Rab.28 The authors further demonstrated that deletion
of either TRAPPC9 or both TRAPPC9 and TRAPPC10 did not affect
membrane traffic but resulted in the appearance of lipid droplets.
TRAPPC9 (called NIBP) was detected in a yeast two-hybrid screen as
an interacting partner of the signaling kinase NIK, and was also found
to interact with the β-subunit of the kinase IKK (IKKβ),85 both of
which function in the Nuclear Factor - kappa B (NF-κB) signaling path-
way. Subsequently, a number of studies have implicated TRAPPC9/
NIBP in NF-κB signaling, with a possible role in cancer
metastasis.86–89
Although the structure of TRAPPC9 is not known, several studies
have addressed aspects of its structure. The amino-terminal portion of
the protein (amino acids 117-411) is predicted to adopt an α-solenoid
structure with multiple tetratricopeptide repeat (TPR) domains.90 Such
repeats are known to be involved in protein-protein interactions.91
The carboxy portion of the protein is predicted to contain two ASPM,
SPD-2, Hydin (ASH) domains,90 believed to target proteins to the cil-
ium.92 A computational model of TRAPPC9 was built using a con-
served metalloprotein from Bacillus cereus.93 Although largely helical,
which would be consistent with the predicted TPR and ASH domains,
the modeled structure was not reported to have these domains.
A number of variants in TRAPPC9 have now been reported
(Table 3). With the exception of a single report where the affected
individual had bigenic TRAPPC9 and PDE3A variants,94 all individuals
with biallelic variants in TRAPPC9 have a strikingly common pathology.
These individuals all display NS-ARID and postnatal microcephaly.
Most are reported to have minimal to no speech and behavioral prob-
lems. Some individuals also display abnormalities in the brain such as
thinning of the corpus callosum, reduced white matter volume and
myelination defects. In addition to these individuals, an individual with
a larger homozygous deletion on chromosome 8 encompassing only
the TRAPPC9/NIBP gene was reported, with a phenotype similar to
those with TRAPPC9 variants.95 Another individual, identified by
homozygosity mapping, had a form of autosomal recessive mental
retardation that mapped to the TRAPPC9 gene on chromosome 8.96
Although a number of genes have been linked to NS-ARID,97
TRAPPC9 is unique in that it is the only gene that has been linked to
this disorder in more than five families.93,97 There are several reasons
that support the notion that dysregulation of the NF-κB pathway may
be a contributing factor in the pathology of individuals with TRAPPC9
variants. First, there is a growing amount of literature on the involve-
ment of TRAPPC9 in the NF-κB signaling pathway.85–89,98 Second,
this pathway is documented to be important for brain function and
development.99,100 Third, while TRAPPC9 is expressed in a variety of
tissues, with the highest being muscle, there is a significant level of
the transcript in brain.85 Fourth, another gene implicated in NS-ARID
also impacts NF- κB signaling.101 Thus, it is tempting to speculate that
variants in TRAPPC9 affect the NF-κB pathway leading to NS-ARID.
However, as detailed below, variants in other TRAPP proteins share
some of these clinical features, particularly intellectual disability, brain
abnormalities and microcephaly. It is possible that there is a wide
range of levels of intellectual disability in individuals with TRAPP gene
variants and, indeed, there is a rather large spectrum of intellectual
disabilities in general. As one of the striking features of TRAPPC9
depletion is an increase in lipid droplet formation,28 it is unclear how
this links to NF-κB signaling and intellectual disability.
3.6 | TRAPPC11 (MIM 614138)
In an effort to address whether TRAPPC2 and TRAPPC2L associate
with different components of TRAPP, each was appended to a tan-
dem affinity purification tag and purified from HeLa cell lysates.17 In
addition to identifying proteins that were homologous to known yeast
TRAPP subunits (see Table 2), several additional proteins were identi-
fied. One of these proteins was called TRAPPC11 (also called
c4orf41). The protein is 1133 amino acids in length and does not have
a recognizable homologue in the yeasts S. cerevisiae and Schizosac-
charomyces pombe but is found in metazoans. Like other TRAPP-
associated proteins, depletion of the protein by RNA interference
resulted in a fragmented Golgi.17 In addition, depletion of the protein
arrested a marker protein that normally traverses the secretory path-
way in a pre-Golgi compartment that was suggested to be either the
ERGIC or ER exit sites. The latter result is consistent with a recent
study that suggested a role for TRAPPC12, a protein found in the
same TRAPP complex as TRAPPC11, in recruitment of the outer layer
of the COP II coat to the ER.19 In another study employing a different
marker protein, ER exit was unaffected and the marker protein was
arrested in the Golgi,102 suggesting TRAPPC11 may function in more
than one step of membrane trafficking. Depletion of the Drosophila
melanogaster TRAPPC11 homologue, called gryzun,103 was shown to
alter the localization of a cell-surface marker, suggesting a defect in
Golgi function.102 The Danio rerio homologue of TRAPPC11 was found
in a zebrafish genetic screen aiming to identify genes involved in liver
disease.104 Indeed, owing to the hepatomegaly seen in the zebrafish
TRAPPC11 mutant, the gene was referred to as foie gras (fgr). Closer
SACHER ET AL. 13
inspection revealed that the livers in the fgr mutant zebrafish accumu-
lated a substantial amount of lipids.
Although the three-dimensional structure of TRAPPC11 has not
been solved, the protein has a region of high conservation that has
been referred to as the foie gras domain. Bioinformatic analysis
reveals that this domain harbors several regions that may assume a
TPR structure. In addition, the protein also has a carboxy-terminal gry-
zun domain whose function remains unknown.
A recent study implicated human and zebrafish TRAPPC11, to the
exclusion of other TRAPP proteins, in N-linked glycosylation.105 The
trappc11 mutant zebrafish had an upregulated unfolded protein
response (UPR). Although protein secretion was defective in the
trappc11 mutant zebrafish, this could not explain the upregulated
UPR because blocking secretion by other means did not result in a
similar UPR. Instead, the trappc11 mutant zebrafish phenocopied
by reducing the levels of lipid-linked oligosaccharides. This was also
found to be the case in the trappc11 mutant fish and, unexpectedly,
genes involved in the synthesis of dolichol (the lipid carrier of the car-
bohydrates) were upregulated in these zebrafish. Because blocking N-
linked glycosylation by tunicamycin treatment of zebrafish results in
fatty liver and an upregulation of the UPR,106 the authors concluded
that fatty liver in the trappc11 mutant zebrafish is induced by a similar
mechanism. Strikingly, in HeLa cells, hypoglycosylation of a resident
ER protein was reported upon depletion of TRAPPC11, but not upon
depletion of any other TRAPP proteins tested. These results suggest
that either TRAPPC11 functions outside of the TRAPP complex or
binds to some factor that is important for lipid-linked oligosaccharide
synthesis while still within the TRAPP III complex.
The first individuals with TRAPPC11 variants were reported in
2013107 (Table 3). The individuals had homozygous variants resulting
in a missense variant (p.Gly980Arg) or a deletion of a portion of the
foie gras domain (p.Ala372_Ser429del). The former variant was associ-
ated with a limb girdle muscular dystrophy 2S (LGMD2S) and cata-
racts in one individual, while the latter was associated with myopathy,
intellectual deficit, hyperkinetic movements and ataxia. A subsequent
report described another TRAPPC11 variant in which the phenotype
was composed of congenital muscular dystrophy (CMD), hepatic stea-
tosis and cataracts.108 In 2017, Koehler et al identified individuals
with TRAPPC11 variants that also suffered from CMD and further
broadened the phenotype to include achalasia, alacrima and scolio-
sis.109 Siblings with compound heterozygous TRAPPC11 variants (p.
Gln777Pro and p.Phe173Tyrfs13*) and a phenotype similar to those
reported by Liang et al108 were recently reported.110 In addition to
CMD, these latter individuals were also observed to have abnormal
dystroglycan staining. The first documented case of a TRAPPC11 vari-
ant resulting in an α-dystroglycanopathy was recently reported.111
This individual also had liver, eye and brain pathology. Matalonga
et al reported an individual with a TRAPPC11 variant that resulted in
N- and O-linked glycosylation defects reminiscent of a congenital dis-
order of glycosylation, with hypotonia but no myopathic changes, and
brain atrophy.112 Several other individuals with confirmed variants in
TRAPPC11 have been identified but yet to be reported in the litera-
ture (Table 3). The phenotypes of these individuals resemble those of
most other TRAPPC11 variants including LGMD, weakness and
cognitive impairment. When reported, creatine kinase (CK) levels were
elevated in individuals with TRAPPC11 variants, further indicative of a
muscle pathology.107,108,110,111 A recent case report described individ-
uals with a compound heterozygous variant in TRAPPC11 who only
present with LGMD2S but none of the other neuromuscular, ocular or
hepatic phenotypes found in other individuals.113 Analysis of all
known TRAPPC11 variants indicates residues and regions of the pro-
tein that are important for function (Figure 3). These include the foie
gras domain and residues near it, Gly980 and the extreme carboxy-
terminus of the protein.
Collectively, variants in TRAPPC11 appear to affect muscle, eye,
brain and to some extent liver. Muscle and brain involvement (in the
form of cognitive impairment), and to a lesser degree eye defects, are
commonly seen in forms of muscular dystrophy, particularly when
caused by variants in either α-dystroglycan (αDG) or genes required
for its proper glycosylation.114 This is due to the fact that the unique
O-linked glycans on αDG are responsible for interactions with the
extracellular matrix (ECM).115 Thus, it is significant that αDG changes
were reported in two individuals with TRAPPC11 variants110,111
because the phenotypes of many of the TRAPPC11 individuals are
similar to those of individuals with dystroglycanopathy. How
TRAPPC11 might be involved in the muscular phenotypes is not clear
and several possibilities can be envisioned. First, given its recently
reported role in the production of lipid-linked oligosaccharides,105
necessary for both N- and O-linked glycosylation, defects in
TRAPPC11 may inhibit the proper glycosylation of αDG by reducing
levels of dolichol-linked carbohydrates, thus preventing αDG from
forming stable interactions with the ECM. Second, given its role in
membrane traffic, particularly at the level of the Golgi, TRAPPC11 var-
iants may alter the trafficking and localization of several key Golgi
enzymes necessary for the unique glycans that enable αDG to interact
with the ECM. Such enzymes include POMT1 and 2, LARGE1 and
2, and POMGNT2 to name a few.116 Finally, TRAPPC11 has been
implicated in autophagy44 (D. Stanga and M. Sacher, unpublished
data), and this process is involved in several forms of muscular dystro-
phy.117 Thus, with TRAPPC11 functioning in several different cellular
FIGURE 3 Schematic of the location of all known TRAPPC11
variants. A cartoon of TRAPPC11 indicating the foie gras (amino acids263-521) and gryzun (amino acids 1036-1095) domains is shown.Variants listed in black and bold represent homozygous variants. Notethat Q797* is a presumed compound heterozygous variant but thesecond variant is unknown. Compound heterozygous variants aredepicted in the same color and the same level away from the cartoon.Most variants fall within and near the foie gras domain and near thecarboxy-terminus, suggesting important functions for these regions ofthe protein
14 SACHER ET AL.
processes, identifying how it results in muscle, eye and brain patholo-
gies will require further dissection of its functions and the use of alter-
native model systems to study muscle biology.
3.7 | TRAPPC12 (MIM: 617669)
Another complex-specific protein is TRAPPC12 (also known as
TTC15, TRAMM and CGI-87). This protein is found in metazoa but
does not have a recognizable homologue in yeast. It was first identi-
fied in a human autophagy proteomic study44 and subsequently char-
acterized as a component of the human TRAPP complex.17 It was
suggested to be a component of the human TRAPP III complex by vir-
tue of its co-purification with TRAPPC8, but not with TRAPPC9 or
TRAPPC1018 (see Figure 1).
Although the structure of TRAPPC12 is yet to be solved, the pri-
mary protein sequence indicates the existence of four conserved TPR
motifs localized close to its carboxy-terminus that likely facilitate its
interaction with other proteins.91 Within the amino-terminal ~200
amino acids there is a region that was shown to be
phosphorylated,118–120 and some of these phosphoresidues appear to
regulate the function of the protein.121
Immunofluorescence experiments revealed that the protein is dis-
tributed as punctae mainly in the cytoplasm and on ER exit sites, and
partially co-localizes with the Golgi.17,19,121 Furthermore, traces of the
stained protein were also visible in the nucleus, a finding confirmed by
subcellular fractionation, biochemical techniques and fluorescence
microscopy.121
The TRAPPC12 protein was demonstrated to be involved in ER-
to-Golgi transport, the regulation of Golgi integrity and autop-
hagy.17,44,122 More recently, a function for the protein in mitosis was
also revealed.121 Depletion of TRAPPC12, but not of any other
TRAPP-associated protein, resulted in a significant increase in the
mitotic index due to a defect in chromosome congression and activa-
tion of the spindle assembly checkpoint. TRAPPC12 associated with
metaphase chromosomes and weakly localized to their kinetochores
where it was shown to be involved in the recruitment of several kinet-
ochore proteins, most dramatically that of CENP-E. Size exclusion
chromatography demonstrated that during mitosis TRAPPC12 was
phosphorylated and no longer co-fractionated with the TRAPP com-
plex. The role of TRAPPC12 in mitosis is likely conserved because an
association of chicken TRAPPC12 with mitotic chromosomes was also
reported.123
Recently, three individuals from two unrelated families harboring
two different TRAPPC12 variants were reported.124 One of them has
a homozygous truncating variant (p.Glu49Argfs*14) resulting in the
absence of full-length protein. The other two individuals are siblings
that harbor two compound heterozygous variants (p.Glu121Argfs*7
and p.Ala627Val). These variants also result in an absence of full-
length protein, suggesting that the missense p.Ala627Val variant in
one of the TPR motifs destabilizes the protein. Importantly, all three
individuals displayed similar clinical phenotypes including global devel-
opmental delay, severe disability, microcephaly, hearing loss, spastic-
ity, brain atrophy and encephalopathy. Similar to HeLa cells depleted
of TRAPPC12,17,121 fibroblasts derived from all three individuals
showed a fragmented Golgi that was rescued by expression of wild-
type TRAPPC12,124 confirming that the phenotype was due to dys-
functional TRAPPC12. Cargo transport from the ER to and through
the Golgi was delayed. In addition, a delay in mitosis was also
observed in fibroblasts from all three individuals. These results are
consistent with the reported functions of TRAPPC12 in membrane
traffic and mitosis.17,121 While a defect in mitosis cannot be ruled out
as a contributing factor in the clinical pathology, given the overlapping
phenotypes with other TRAPP variants, at least part of the pathology
is likely due to a membrane trafficking defect.
4 | TRAPPOPATHIES: CONVERGENCE ANDDIVERGENCE OF PHENOTYPES
Causality in genetics is often difficult to assign. It is generally
accepted, however, that co-segregation of a phenotype with variants
in a particular gene, and/or studies using a wild-type protein to cor-
rect a cellular phenotype in cells derived from affected individuals
allows causality to be suggested.125,126 The more individuals showing
such co-segregation the stronger the suggestion of causality. With
this in mind, the only other multisubunit tethering factor in which vari-
ants in a large number of subunits have been linked to human disease
is the conserved oligomeric Golgi (COG) complex (Table 4). This com-
plex is composed of eight subunits termed COG1-COG8 that are
organized into two “lobes”: lobe A composed of COG1-COG4 and
lobe B composed of COG5-COG8.127 Variants in seven of the eight
genes that encode these subunits all result in some form of congenital
disorder of glycosylation (CDG), suggesting that impairment of COG
subunits results in impairment of the function of the entire complex.
In contrast, variants in the genes encoding TRAPP proteins result
in phenotypes that, in some cases, are protein-specific. While all vari-
ants in TRAPPC2 are associated with the skeletal defect SEDT, no
other TRAPP gene variant results in a similar skeletal defect, nor have
there been any reports of TRAPPC2 variants associated with any other
phenotype. This suggests that impairment of TRAPPC2 function does
not necessarily affect TRAPP complex function but rather impacts a
TRAPPC2-specific function. As this protein has been implicated in
both regulating the cycling of the GTPase Sar154 and in a nuclear-
specific function,50,52 a function outside of the confines of TRAPP
complexes can be envisioned, perhaps resulting in the unique clinical
pathology.
Variants in TRAPPC11 are linked to muscular disorders including
LGMD2S, CMD and generalized myopathy. This is supported by the
elevated levels of CK in these individuals. In addition, cataracts and
liver involvement have also been reported in some of these individ-
uals. All of the above phenotypes are TRAPPC11-specific. A link
between muscular defects and eye involvement is known, particularly
for dystroglycanopathies.114 Regarding the liver pathology, it has been
shown that TRAPPC11 is involved in lipid-linked oligosaccharide syn-
thesis and upregulation of the UPR.105 This function of TRAPPC11 is
unique and was not observed for other components of the TRAPP
complex. The TRAPPC11-induced UPR includes upregulation of the
transcription factor ATF6, overexpression of which is known to result
in fatty liver.128 Thus, some of the clinical manifestations of
TRAPPC11 variants can be attributed to this unique function of
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How to cite this article: Sacher M, Shahrzad N, Kamel H,
Milev MP. TRAPPopathies: An emerging set of disorders
linked to variations in the genes encoding transport protein