FEBS Letters xxx (2015) xxx–xxx

journal homepage: www.FEBSLetters.org

Review

Bardet–Biedl syndrome: Is it only cilia dysfunction?

Rossina Novas a, Magdalena Cardenas-Rodriguez a, Florencia Irigoín a,b, Jose L. Badano a,⇑
a
Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo CP11400, Uruguay
b
Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Gral. Flores 2125, Montevideo CP11800, Uruguay

a r t i c l e i n f o a b s t r a c t

Article history: Bardet–Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder, characterized by
Received 2 July 2015 both congenital and late onset defects. From the analysis of the mutational burden in patients to the
Revised 14 July 2015 functional characterization of the BBS proteins, this syndrome has become a model for both under-
Accepted 15 July 2015
standing oligogenic patterns of inheritance and the biology of a particular cellular organelle: the
Available online xxxx
primary cilium. Here we briefly review the genetics of BBS to then focus on the function of the
Edited by Wilhelm Just BBS proteins, not only in the context of the cilium but also highlighting potential extra-ciliary roles
that could be relevant to the etiology of the disorder. Finally, we provide an overview of how the
Keywords:
study of this rare syndrome has contributed to the understanding of cilia biology and how this
Bardet–Biedl syndrome knowledge has informed on the cellular basis of different clinical manifestations that characterize
Cilia BBS and the ciliopathies.
Ciliopathies Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

1. Introduction IFT-B particles are responsible for anterograde transport (toward

Bardet–Biedl syndrome (BBS; MIM 209900) is a genetic pleio-
tropic condition characterized by retinal degeneration, obesity,
postaxial polydactyly, mental retardation, hypogonadism and renal
malformations, although patients can present a number of addi-
tional clinical manifestations including asthma, craniofacial
defects, anosmia, hearing loss and diabetes [1]. Studies in humans,
animal models, cells, and bioinformatics have shown that the cel-
lular basis of BBS is intimately linked to the dysfunction of a partic-
ular cellular organelle, the primary cilium.
Cilia are evolutionary conserved, microtubule-based organelles
that are organized from a modified centriole, the basal body, and
that emanate from the plasma membrane of most cells in verte-
brates. In a simplistic classification, two main types of cilia can
be distinguished: motile and primary cilia whereby motile cilia
are composed by an axoneme of 9 pairs of outer microtubule dou-
blets surrounding a central pair (9 + 2) while primary cilia present
a 9 + 0 structure. In addition, while cilia and flagella (same ultra-
structure) are motile, primary cilia are generally immotile and pre-
sent as a single structure on the apical surface of cells. A
mechanism that is critical for building, maintaining and reab-
sorbing cilia is intraflagellar transport (IFT), the movement of
material into and out of the cilium that is carried out by IFT parti-
cles linking their cargoes to microtubule based molecular motors.
the ciliary tip) whereas IFT-A directs retrograde movement
(toward the cell body) in association with kinesin and dynein
motors respectively (Fig. 1; reviewed in [2,3]).
A large body of work has shown that primary cilia participate in
cell signaling, sensing and transducing a host of inputs ranging
from mechanical cues to chemical and paracrine signaling includ-
ing Hedgehog, Wnt and PDGF (Fig. 1; reviewed in [4–6]). Not sur-
prisingly then, primary cilia play a critical role during development
and in maintaining cellular and tissue homeostasis, a fact that is
most clearly highlighted by the consequences of cilia dysfunction.
While complete absence of cilia is incompatible with life, defective
ciliary function has been associated with a number of clinical
entities ranging from polycystic kidney disease (PKD) and
nephronophthisis (NPHP) to pleiotropic conditions such as BBS,
Alström syndrome (ALMS), Joubert syndrome (JBTS), and Meckel
Gruber syndrome (MKS), all members of a novel human disease
category: the ciliopathies [7,8]. The ciliopathies encompass a range
of clinically distinct entities that share, to varying degrees, a com-
mon cellular basis. In this review, we will focus on a model ciliopa-
thy, BBS, discussing the genetics of the syndrome and the known
roles of the BBS proteins both in the context of the cilium but
importantly also outside of the organelle.
2. The genetics of BBS

BBS is a genetically heterogeneous condition for which 19 BBS

⇑ Corresponding author. Fax: +598 522 4185.
genes have been identified to date: BBS1-12, BBS13/MKS1,
E-mail address: jbadano@pasteur.edu.uy (J.L. Badano).

http://dx.doi.org/10.1016/j.febslet.2015.07.031
0014-5793/Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031
2 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx

A Kinesin
B
GLI GLI
ANTEROGRADE

RETROGRADE
Dynein

TRANSPORT
TRANSPORT IFT complex A/B

A B
A B
PDGF Canonical
PDGFRα Wnt
Other Wnt
receptors? Wnt PCP
A B

A B
GLI
Frizzled

PC1/PC2 Complex
Ca2+ Ca2+ FLUID FLOW Basal Body
(BBSs, NPHP)
A B

Ca2+
Smo Ca2+

PDGF signaling Balance Canonical/PCP

A B

signaling
Hedgehog GLI
activation
TRANSITION ZONE WITH TRANSITION FIBRES
Shh
B A (NPHP, MKS, CEP290)
A
B
Ptch1 A
Basal Body Ca2+ signaling Proliferation
GLI
Differentiation
Smo
Tissue homeostasis
Organogenesis
Activation of Hh target
genes (nucleus)

Fig. 1. Schematic representation of the cilium and its role in signal transduction. The cilium is composed by a microtubule axoneme organized from a basal body. Alongside
the microtubules, IFT particles and motors are in charge of transporting moieties in and out of the cilium. Different receptors localize to the ciliary membrane and rely on the
cilium for signal transduction to control several biological processes (A and B). One of the best characterized is the Hedgehog signaling pathway (A). Upon binding of the
activator (Shh) to its receptor Ptch1, the complex is translocated outside of the cilium and no longer inhibits the ciliary entry of Smo, which in turn facilitates Gli processing
and activation. Activated Gli transcription factors (Gli-star) exit the cilium and enter the nucleus to drive gene transcription. (B) Basal body proteins, such as the BBSs and
NPHPs, are involved in regulating Wnt signaling whereby depletion of BBSs results in increased canonical signaling and reduced PCP.

BBS14/CEP290, BBS15/WDPCP/FRITZ, BBS16/SDCCAG8, BBS17/LZTFL1,
BBS18/BBIP10/BBIP1 and BBS19/IFT27; ([9–14] and references
within). This heterogeneity was originally thought to be the cause
of the significant inter-familial variability that characterizes the
syndrome. However, establishing genotype–phenotype correla-
tions has been a challenge, likely due to the significant functional
overlap between the BBS proteins that we will discuss in the fol-
lowing sections. Having said that, thorough analyzes of different
BBS patient cohorts and animal models are demonstrating subtle
differences in disease presentation that are likely due to specific
functions of different BBS proteins. For example, studies suggest
that mutations in BBS2, BBS3 and BBS4 are associated with charac-
teristic ocular phenotypes [15,16] and patients bearing mutations
in BBS16/SDCCAG8 are characterized by highly penetrant renal dis-
ease but do not present with polydactyly [13]. Similarly, patients
with mutations in BBS6, BBS10 or BBS12 present with a more severe
renal phenotype [17]. Importantly, BBS6, BBS10 and BBS12 belong
to a functionally distinguishable subgroup of BBS proteins, a fact
that could provide a molecular explanation to this finding
[18,19]. Studies in mice are also highlighting differences linked to
the identity of the mutated gene. Bbs3 / mice develop common
features of Bbs mutants, such as increased body weight and retinal
degeneration, but also distinct manifestations, such as severe
hydrocephalus and increased blood pressure [20]. Likewise,
Bbs4 / and Bbs6 / mice present differences in blood pressure
compared to Bbs2 / animals [21].
BBS is also characterized by significant intra-familial variability,
a phenomenon not readily explained by genetic heterogeneity.
Although BBS is largely inherited as an autosomal recessive trait,
the screening of patient cohorts showed that in some families
the disorder behaves as an oligogenic condition whereby mutant
alleles in more than one BBS gene and other modifier loci interact
to modulate the penetrance and expressivity of the syndrome
[11,22–30]. Thus, differences in the total mutational load across
different BBS associated genes likely contribute to the characteris-
tic phenotypic variability in this syndrome [31,32].
The functional characterization of the BBS proteins has provided
critical information to understand both the overall lack of
genotype-phenotype correlations and the genetic interaction
between different BBS genes. These proteins share biological func-
tions and even work forming multi-protein complexes. Therefore,
mutations in different BBS genes are likely to affect the same bio-
logical processes (i.e. the formation/function of the cilium) and
thus correlations between mutations in specific BBS genes and
subsets of phenotypes would not be expected and rather would
only be explained by specific functions of individual BBS proteins.
Likewise, the observation of oligogenic inheritance in BBS is likely a
consequence of mutating different components of the same protein
complex, where different subunits can at least partially compen-
sate for the lack of another, or affecting the same biological path-
way at more than one step, models that have been used to
explain this type of genetic interactions (reviewed in [22,33]).
Interestingly, oligogenicity is not restricted to BBS but appears to
be relatively common among ciliopathies as examples have been
documented or postulated for NPHP, MKS and Acrocallosal
(ACLS) syndrome [34–36].
The ciliopathies encompass a range of human conditions that
although clinically distinct, share significant aspects of both their
phenotypic presentation and their cellular basis. In other words,
mutations in genes associated with different disorders can result
in similar phenotypes because they affect the same organelle.
Thus, if all the ciliopathies are caused by cilia dysfunction, why
are these disorders distinct clinical entities? The main factor is
the identity of the mutated gene and the specific function of its
encoded protein in the cilium. It is not the same to impair cilia for-
mation than to affect a given ciliary channel or receptor. In

Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031
 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx 3

addition, accumulating evidence is showing that the type of muta-
tion and the degree of residual protein function, together with the
mutational load across both bona fide ciliopathy genes and modi-
fier loci can determine both the clinical entity and its presentation
[31,32]. Therefore, a given gene can be causally related to more
than one ciliopathy (Table 1). For example BBS14/CEP290 muta-
tions have been found associated not only with BBS but also with
MKS, NPHP, JBTS and other ciliopathies, and mutations in MKS
genes can cause BBS [4,11,37–39]. Lastly, one largely overlooked
aspect of this equation is that specific cilia-associated proteins
might play extra-ciliary roles that could also contribute to the
pathogenesis and presentation of the ciliopathy, a factor that we
will discuss for the BBS proteins in following sections.
3. The role of the BBS proteins... in the cilium
The initial link between BBS and primary cilia came from the
identification of a homozygous null mutation in BBS8 in a family
presenting situs inversus, a reversal in the left–right (LR) configura-
tion of the body plan [40]. Perturbations in the establishment of LR
are caused by defects at specific embryonic structures, LR organiz-
ers, such as the node in the mouse and the Kupffer’s vesicle in
zebrafish, where cilia play a key role generating asymmetries
[41]. The characterization of BBS8 then showed that the protein
localizes to the centrosome and basal body of cilia [40], and subse-
quent studies have shown that the vast majority of BBS proteins
share this localization pattern and can also enter the organelle
(Table 1; [24,40,42–47]).
3.1. The BBS proteins in ciliogenesis: the BBSome
The link between the BBS proteins and the cilium supported the
initial expectation, raised by the genetic analysis of BBS cohorts,
that this group of seemingly unrelated proteins could display sig-
nificant similarities at the functional level. This notion was further
reinforced by the realization that several of the BBS proteins phys-
ically interact to form a complex that has been dubbed the
BBSome.
The BBSome is a 438kDa complex composed by eight BBS pro-
teins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and
BBIP10/BBS18) that functions as a coat for vesicles destined to
the cilium [14,47,48]. Furthermore, it has been shown that the
BBSome recognizes ciliary targeting signals in cargo proteins thus
sorting and trafficking membrane proteins to the primary cilium

Table 1
BBS genes: their function, localization, and association to BBS and other ciliopathies.

Association Ciliary role Extra ciliary role? Localization

with other
ciliopathies
BBS1 Member of the BBSome Notch recycling. Regulate RNF2 levels Centrosome/basal body/cilia
BBS2 MKS Member of the BBSome (core) Regulate RNF2 levels Centrosome/basal
body/cilia/nucleus
BBS3/ARL6 Small GTPase. BBSome assembly and traffic Intracellular trafficking? Cytoplasm/Cilia
BBS4 MKS Member of the BBSome. Recruits the BBSome to the Notch recycling. Targets cargo to the pericentriolar Centrosome/basal body/
cilium region. Regulates actin polymerization. pericentriolar
Transcriptional regulation (RNF2) region/centriolar satellites
BBS5 Member of the BBSome Centrosome/basal
body/cilia. Direct contact
with the ciliary membrane
BBS6/MKKS MKS, MKKS BBS-chaperonin complex that assist in BBSome Possible role in cell cycle. Regulates actin Centrosome/basal
assembly polymerization body/cytoplasm
BBS7 Member of the BBSome (core) Transcriptional regulation (RNF2). Proteasome Centrosome/basal
body/cilia/nucleus
BBS8 Member of the BBSome Regulates actin polymerization. Membrane Centrosome/basal
localization of Vangl2 body/cilia/focal adhesions
BBS9 Member of the BBSome (core) Centrosome/basal
body/cilia/focal adhesions
BBS10 BBS-chaperonin complex that assist in BBSome Centrosome/basal body
assembly
BBS11/TRIM32 Similar to E3 ubiquitin ligase. Possible role in Predominantly present at
proteasome degradation the cytoplasm/nucleus
BBS12 BBS-chaperonin complex that assist in BBSome Centrosome/basal
assembly body/cytoplasm
BBS13/MKS1 MKS Transition zone organization Centrosome/basal
body/transition zone
BBS14/CEP290/ JBTS, MKS, Transition zone organization. Assembly and ciliary Centrosome/centriolar
NPHP6 SLS, NPHP, entry of the BBSome satellites/basal
LCA body/transition zone
BBS15/WDPCP/ MKS Recruitment of proteins essential for ciliogenesis PCP effector protein. Cell migration, cell polarity Transition zone/cytoplasm/
FRITZ by modulation of the actin cytoskeleton actin cytoskeleton and focal
adhesions.
BBS16/SDCCG8/ SLS, NPHP Regulates centrosomal accumulation of DNA damage response. Centrosome organization Transition zone/centrosome
NPHP10 pericentriolar material during interphase and mitosis. associated protein.
BBS17/LZTFL1 BBSome-interacting protein. Regulates ciliary Cytoplasmic protein.
trafficking of BBSome components and Smo
BBS18/BBIP10/ Member of the BBSome. Required for BBSome and Required for cytoplasmic microtubule Cilia
BBIP1 primary cilium assembly polymerization and acetylation (MT stability)
BBS19/IFT27 Component of the IFT-B complex required for Cilia
anterograde transport of ciliary proteins. Links the
BBSome to the IFT machinery

MKS: Meckel–Gruber syndrome; JBTS: Joubert Syndrome; NPHP: nephronophthisis; SLS: Senior–Løken syndrome; LCA: Leber congenital amaurosis; MKKS; McKusick-
Kaufman syndrome.

Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031
4 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx
such as the G protein coupled receptors somatostatin receptor type
3 (Sstr3) and melanin-concentrating hormone receptor 1 (Mchr1)
(Fig. 2A; [48,49]). Therefore, the BBSome plays a critical role regu-
lating cilia composition. In addition, evidence is showing that the
BBSome plays a role in IFT likely by coating the IFT particles (see
below).
The assembly of the BBSome coat onto membranes is triggered
by the small Arf-like GTPase ARL6/BBS3, which is activated upon
GTP binding [48]. Moreover, the BBSome interacts with the small
GTPase Rab8 via Rabin8, its guanosyl exchange factor (GEF).
Importantly, Rab8 plays a role in the docking and fusion of
post-Golgi vesicles to the base of the cilium, and enters the cilium,
suggesting that it is critical to mediate the targeting of the BBSome
to the cilium [47,50]. In addition, it was demonstrated that the
BBSome subunit BBIP10/BBS18 affects microtubule polymerization
and acetylation, a post-translational modification highly prevalent
in cilia microtubules, suggesting that the BBSome might partici-
pate in cilia formation/maintenance both by regulating cilia mem-
brane composition and microtubule dynamics [51].
The role of the BBS proteins in the context of the cilium has
been the main attraction of this group of proteins and the func-
tional characterization of at least some of the ‘‘non-BBSome’’ BBS
proteins has further reinforced this cilia-centric view. As
mentioned above, BBS3/ARL6 plays a critical role in the function
of the BBSome. BBS6, BBS10 and BBS12 compose the
BBS-chaperonin complex, which mediates the assembly of the
BBSome together with CCT/TRiC chaperonins [19]. Interestingly,
the assembly of the BBSome occurs in several steps involving the
formation of intermediate structures (Fig. 2B; [52]). The
CCT/TRiC/BBS-chaperonin complex first binds and stabilizes BBS7
and its interaction with BBS2 and BBS9 to form a BBSome core to
which then the rest of the proteins are incorporated in an orderly
fashion: BBS1, BBS5, BBS8 and lastly BBS4, to which BBIP10 then
binds [51,52].
Understanding the order in which BBS proteins are incorpo-
rated into the BBSome is likely to provide clues to dissect putative
specific functions of individual BBS proteins. Interestingly, both
BBS8 and BBS4, two tetratricopeptide repeat (TPR) containing pro-
teins with significant similarity [40,43], are incorporated at the end
of the assembly process. TPRs are typically involved in protein–
protein interactions and thus these BBS proteins could serve as
adaptors or provide target specificity to the BBSome.
Interestingly, BBS4 has been shown to interact directly with a
number of proteins that are relevant to the function of the
BBSome and the pericentriolar region (see below).
3.2. Recruiting the BBSome to the cilium: the role of the pericentriolar
region
Besides the role of Rab8 mediating the cilia targeting of the
BBSome, the pericentriolar region and centriolar satellites appear
to play a major role in this process. BBS4 and the BBSome interact
with PCM1, the main component of pericentriolar satellites
[43,47]. BBS4, binding the p150Glued subunit of the dynein/dynactin
molecular motor, is required to transport PCM1 toward the peri-
centriolar region (Fig. 2C; [43]). Importantly, recent evidence is
showing that this interaction might coordinate the availability of
BBSome subunits with ciliogenesis.
During ciliogenesis BBS4 relocalizes from the centriolar satel-
lites to the cilium in a process that is mediated by
Cep72/Cep290: Cep72 binds PCM1 and in turn recruits Cep290
(BBS14) and this interaction has been shown to keep Cep72 and
Cep290 in the satellites and away from the centrosome [53].
PCM1 appears to regulate the centrosomal/basal body availability
of Cep72/Cep290 and consequently that of BBS4 (Fig. 2D). In addi-
tion, BBS8 ciliary localization is also reduced upon depletion of
Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031
Cep72/Cep290 suggesting that failure of BBS4 to re-localize to
the cilium impairs recruitment of BBS8 and likely the BBSome
[53]. BBS4 also interacts with AZI1, another component of centrio-
lar satellites, and depletion of AZI1 results in the accumulation of
the BBSome in the cilium [54], therefore reinforcing the notion that
pericentriolar satellites regulate the availability of BBSome sub-
units, in particular BBS4, for the recruitment of the BBSome to
the cilium.
Cep290/BBS14 not only localizes to centriolar satellites but is
also an integral part of the transition zone, the proximal region
of the cilium that plays a critical role in mediating trafficking of dif-
ferent moieties into the ciliary compartment [55,56]. At this level,
Cep290 and NPHP5 mediate both the assembly and ciliary entry of
the BBSome [57]. Other BBS related proteins such as MKS1/BBS13
and SDCCAG8/BBS16/NPHP10 also localize to the transition zone
reinforcing the importance of this region for the function of the
BBSome [11,13]. In addition, the novel centriolar satellite SSX2IP
targets CEP290 to the transition zone and SDCCAG8/BBS16, a pro-
tein that interacts with PCM1, regulates the recruitment of peri-
centriolar material to the centrosomal region, thus further
highlighting the critical role of the pericentriolar region in
BBSome function and cilia biology [58,59].
3.3. Inside the cilium: the BBSome and IFT
In Caenorhabditis elegans, mutations in bbs-7 and bbs-8 result in
shortened cilia and both genes are required for the correct move-
ment of the IFT components OSM-5/Polaris and CHE-11, but not
CHE2, suggesting that the BBS proteins could participate in IFT
and play a role facilitating transport of a subset of these proteins
[46]. In the nematode, anterograde IFT is carried out by the action
of two molecular motors, kinesin-II and OSM-3, and both bbs-7
and bbs-8 are required to coordinate their action and to stabilize
the IFT/motor complex [60]. Interestingly, it was postulated that
the BBSome could function as a coat adaptor for IFT [47]. Later
work shows that the BBS proteins participate in the assembly
and remodeling (disassembly and reassembly) of IFT complexes,
both at the base of the cilium and the ciliary tip [61]. Wei and col-
leagues performed a whole-genome mutagenesis screen in C. ele-
gans and identified mutations in dyf-2 (homolog of the IFT-A
component IFT144) and bbs-1 in worms presenting normal antero-
grade IFT but defective IFT remodeling at the cilia tip. In dyf-2
mutants the BBSome subunits accumulate at the ciliary base
despite unaffected anterograde IFT. The authors present a model
in which the BBSome participates in the assembly of IFT particles
at the ciliary base, it is then transported as IFT cargo to the tip of
the cilium, and there, together with IFT-A, organize retrograde
transport (Fig. 2E; [61,62]). However, the requirement of BBS pro-
teins for IFT might depend on the organism and even cell types.
Like in C. elegans, the BBSome has been recently shown to be part
of IFT complexes in olfactory neurons in a 1:1 stoichiometry with
IFT particles [63]. In contrast, BBS proteins are only found in a sub-
set of IFT particles in Chlamydomonas reinhardtii, and mutations in
key BBSome components do not affect IFT particle assembly and
trafficking, albeit functional defects and accumulation of signaling
proteins are observed [64].
3.4. Exiting the cilium: the BBSome and IFT27/BBS19
Exiting the cilium is important for IFT regulation as well as
cilia-mediated signaling. For example, the BBSome has been shown
to mediate the ciliary exit of Patched-1 (Ptch1) and Smoothened
(Smo), two components of the Hedgehog (Hh) pathway, and deple-
tion of Bbs proteins in mice result in decreased Shh signaling
[65,66]. The identification of IFT27 as BBS19 [9] provided a key
 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx 5

B Arl6
A
BBSome IFT27

Arl6 BBSome BBSome

BBSome
A B

BBSome
BBSom
A B
Arl6
Ciliary membrane
proteins
E

BBSome

BBSome
(Sstr3, Mchr1,

BBSom
others) TRANSITION ZONE WITH TRANSITION FIBRES
B A
A (NPHP, MKS, CEP290)
Arl6 BBSom
BBSome BBSome B
EXIT
ENTRY A (IFT27)
(ARL6 Basal Body PERICENTRIOLAR REGION
CEP290 (BBS, CEP290,
BBSome NPHP5 NPHP5)
LZTFL1) CENTRIOLAR SATELLITES
BBIP10 PCM1 (PCM1, BBS4, CEP72/290, AZI1)
BBS5 BBS2 BBS4 BBS4
A BBS8
BBS7 BBS1
D
BBS4

BBS4
PCM1
Arl6
BBS9 PCM1
BBS4
C PCM
1
BBSome BBS4 4
RABIN8 BBS lued
G
0
RAB8
8 BBS5 BBS2 p15
BBS7 BBS1
BBS8
post-Golgi vesicle BBS9
CCT/TRiC/
BBS6 BBS10 BBS-CHAPERONIN
BBS2 BBS12 COMPLEX
BBS5
BBS7 BBS1
GOLGI
COMPLEX BBS9 B
BBS2
BBS7 BBS1 BBS2
BBS9 BBS7 BBSome CORE
BBS9

Fig. 2. Schematic representation of the roles reported for the BBS proteins. Summary of the proposed roles for the BBSome in the cilium. (A) The BBSome recognizes and coats
vesicles with transmembrane proteins destined to the cilium. (B) BBSome assembly involves a series of intermediate complexes and is facilitated by the action of the CCT/
TRiC/BBS chaperonin complex (composed of BBS6, BBS10 and BBS12). (C) BBS4 is involved in transporting proteins toward the pericentriolar region in a microtubule and
dynein dependent process. (D) The pericentriolar region appears to act as a reservoir of BBS4 thus controlling BBSome availability. (E) The BBSome participates in the
formation of IFT particles and its transported to the ciliary tip. (F) Disassembly of the BBSome is thought to mediate IFT remodeling at the ciliary tip and the recruitment of
cargo destined for ciliary exit to IFTA particles.

entry-point to start understanding this aspect of BBSome regula-
tion [67–69].
IFT27 (also known as Rabl4) is a small G protein that
heterodimerizes with IFT25 forming a complex (IFT25/27) that
can exist both associated with IFT-B particles or free [70,71].
Eguether and colleagues have shown that Ift25 and Ift27 knockout
mice present with typical hedgehog related structural defects, and
at the cellular level show ciliary accumulation of Ptch1 and Smo
[68]. In addition, they showed that different BBSome components
readily accumulate in cilia of their Ift27 mutants suggesting that
disruption of Ift25/Ift27 results in impaired BBSome exit.
LZTFL1/BBS17 also regulates ciliary trafficking of the BBSome and
Smo [65]. In Ift27 mutants, the BBSome, ARL6/BBS3 and
LZTFL1/BBS17 are found enriched in the cilium suggesting that
IFT27 likely acts removing these proteins from the cilium, and with
them, Ptch1 and Smo [68]. In contrast, depletion of Lztfl1 does not
result in ciliary accumulation of Ift27 prompting the authors to
postulate a model where Lztfl1 acts downstream of Ift27 linking
the BBSome to the IFT machinery (IFT25/27) for ciliary export [68].
Liew and colleagues added mechanistic information demon-
strating a direct biochemical interaction between IFT27 and
ARL6/BBS3 [69]. Again, in both Ift27 knockdown cells and Ift27 /
MEFS, BBSome subunits and components of the hedgehog pathway
accumulate in the ciliary compartment. Importantly, IFT27 sepa-
rates from the IFT-B complex to interact only with the nucleotide
free ARL6/BBS3, thus potentially acting as a regulator of its activity,
a GEF (guanine nucleotide exchange factor) that would promote
ARL6/BBS3 activation [69]. Thus, the authors suggest that the
remodeling of IFT particles at the ciliary tip is started by GTP
hydrolysis of ARL6/BBS3, which leads to disassembly of the

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j.febslet.2015.07.031
6 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx
BBSome. Then, IFT-B particles release IFT25/27 (by unknown
mechanism) and free IFT27 is able to participate in the GDP to
GTP exchange of ARL6/BBS3, thus triggering the assembly of a
BBSome coat linking cargoes destined for ciliary exit with retro-
grade IFT particles (Fig. 2F; [69]).
3.5. The BBS proteins: ciliogenesis and cilia length regulation
Despite the critical role of the BBSome in transporting ciliary
cargo, IFT regulation and overall ciliary function, individual BBS
proteins do not appear to be absolutely required for cilia formation
or cilia length regulation. As already mentioned, bbs-7 and bbs-8
mutations in C. elegans result in shortened cilia and compromised
IFT but cilia are still formed [46]. Bbs7 / mice present fewer and
shorter motile cilia in the ependymal cell layer but do not display
overt cilia defects in the kidney and pancreas [72]. However, Bbs7
mutant animals present sperm with absent or abnormal flagella,
similarly to what is observed in Bbs1M390R/M390R, Bbs2, Bbs4 and
Bbs6 mutant mice, in which cilia do form but animals are sterile
due to sperm flagella defects [72–76]. In cells, depletion of differ-
ent BBSome components does not result in cilia shortening or
absence [51]. Therefore, the requirement of individual BBS proteins
for ciliogenesis and cilia length regulation appears to be highly
variable. This variability could be explained by differences in the
pattern of gene expression for different BBS genes in different cells
and tissues and the requirement/dependency of different cell types
on the function of the BBS proteins for IFT and ciliogenesis. In addi-
tion, functional redundancy among BBS proteins likely explains
why targeting individual BBS genes might not be sufficient to have
a major impact on ciliogenesis. We have shown that CCDC28B, a
protein that interacts with a number of BBS proteins that are inte-
gral components of the BBSome, does play a role in cilia length reg-
ulation whereby its depletion in both cells and zebrafish results in
significantly shortened cilia [77]. At least part of the role of
CCDC28B in ciliogenesis is mediated by its interaction with SIN1,
a member of the mTORC2, albeit independently of this complex.
CCDC28B is a coiled-coil protein that in the context of mTORC2
plays a role mediating complex assembly [78]. Thus, it will be
interesting to study whether this protein and SIN1 participate in
the assembly or function of the BBSome as part of its role in
ciliogenesis.
4. Other roles for the BBS proteins: going beyond the cilium
In addition to their role in cilia, the BBS proteins may have other
roles in cell physiology (Table 1). A first approximation to address-
ing this possibility is to analyze whether there are BBS homologous
genes in non-ciliated organisms. Earlier studies evaluating this
issue showed that at least the BBS genes identified at that time
(BBS1, 2, 4, 5, 6, 7 and 8) were present only in ciliated organisms
[45,74,79]. Accordingly, genes homologous to CCDC28B are present
only in ciliated metazoans [77]. Interestingly however, some BBS
genes are absent from organisms that possess ciliated cells, as it
is the case for bbs2 and bbs7 in Drosophila melanogaster.
Therefore, in certain organisms, some BBS proteins appear to be
dispensable for ciliary function or, alternatively, other BBSs or
BBS-unrelated proteins took their place. The chaperonin-like BBS
proteins (BBS6, BBS10 and BBS12) were considered exclusive of
vertebrates until a recent phylogenetic analysis discovered orthol-
ogous genes in very ancient eukaryotes, including non-ciliated
ones [19,80]. However, the functionality of these genes in
non-ciliated organisms has not been fully explored. Thus, while
these data support a role for BBS genes in cilia function or/and
some other specialized function common to ciliated organisms,
we cannot discard that the BBS proteins could have been recruited
Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031
for other, cilia-unrelated functions. Importantly, this phenomenon
has been described for core members of the IFT machinery that,
although conserved only in ciliated organisms [45,79], have been
shown to be expressed and to be functional in non-ciliated cells
such as lymphocytes [81]. Here we will describe examples where
the BBS proteins might be playing roles that, albeit could be linked
to cilia, are not restricted to the formation and maintenance of the
organelle.
4.1. Intracellular vesicular traffic
The BBSome is involved in delivering membrane proteins to the
cilium but its participation in microtubule dependent trafficking is
likely not restricted to that on route to the organelle. Several
BBSome components have been involved in retrograde,
dynein-mediated, melanosome transport in zebrafish, a process
that is not linked to cilia [82]. BBS1 and BBS4 recycle the Notch
receptor to the plasma membrane [83]. This receptor is present
both at the plasma and ciliary membrane, and it is internalized
after activation. From early endosomes it can be either directed
to multi vesicular bodies for degradation or recycled back to the
plasma membrane [84]. When levels of BBS1 or BBS4 are reduced,
recycling of Notch from early endosomes is diminished, suggesting
that the BBS proteins participate in the trafficking from early endo-
somes to the cell surface (Fig. 3A; [83]). The ciliary pocket appears
as a privileged site for vesicle docking [85], so it is possible that
recycling to the plasma membrane occurs at this site and receptors
are then distributed to the rest of the cell surface. However, it can-
not be discarded that the BBS proteins and the BBSome mediate
receptor recycling to other parts of the cell surface, independently
of the cilium.
Importantly, a more generalized role of cilia proteins in cell traf-
ficking has also been described for bona fide IFT proteins. IFT20
traffics membrane proteins from the Golgi to the cilium and inside
the ciliary compartment but also participates in recycling signaling
molecules to the immune synapse in non-ciliated T-lymphocytes
[81,86]. Moreover, IFT20 and BBS8 have been involved in mem-
brane localization of Vangl2, a protein of the PCP pathway, in a pro-
cess that is not affected by other ciliary proteins and therefore has
been proposed as cilia-independent [87].
As mentioned above BBS3/ARL-6 is a member of the ARF-related
small GTPases, a family of proteins that are associated with mem-
brane trafficking. Some of these GTPases act by promoting the
assembly of protein coats on donor compartments, the first step
in vesicle formation and cargo selection, and BBS3 fulfills this role
mediating BBSome association to membranes and traffic of the
complex into and out of the cilium [48,88]. Consequently, the cil-
iary localization of the BBSome, as well as that of membrane pro-
teins known to be transported by the BBSome (Mchr1 and Smo),
is impaired in the absence of BBS3 [20]. As mentioned earlier
Bbs3 / mice present characteristics that are not readily observed
in other BBS mutants and thus could indicate a broader role for this
protein in intracellular traffic [20]. For example, it was observed
that canonical Wnt signaling seems to be inversely modulated by
BBS3 and members of the BBSome whereby the pathway is acti-
vated when BBS3 is overexpressed [89] or when members of the
BBSome, BBS1, BBS4 or BBS6 are down-regulated [90]. While these
observations suggest that BBS3 may be involved in other cellular
processes that are not related to the BBSome, further experiments
should be performed to determine if these processes are
cilia-independent.
4.2. Regulation of proteasome activity
Proteasome-mediated proteolysis is important for maintaining
appropriate cellular levels of proteins and represents a critical
 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx 7

Notch

Ciliogenesis
regulation
Notch Notch
Recycling Early endosomes
Basal Body
BBS1, BBS4 Notch ? Actin dynamics
A BBSome? BBS11
C
Endosomal BBS proteins
? BBS4
BBS6
B BBS8
Lysosome MVB Proteasome
Degradation

Other RNF2
BBSs??
Degradation Signaling
BBS7 BBS7 ?
BBS2 regulation

Cytoplasm-nuclear ?
shuttling?
D
RNF2 Transcriptional
Other BBS7
BBSs??
BBS7
regulation
BBS2 Nucleus
Fig. 3. Potentially extraciliary roles of the BBS proteins. Schematic representation of putative roles of the BBS proteins that are not necessarily linked to the formation and
maintenance of the cilium. (A) BBS proteins participate in the regulation of endosomal trafficking whereby Notch receptor recycling to the plasma membrane is impaired
upon depletion of BBS1 and BBS4. (B) Several BBS proteins interact with proteasomal subunits and regulate its activity thus potentially affecting signaling. (C) BBS proteins
have been reported to affect actin dynamics, which in turn regulate ciliogenesis. (D) BBS7 and BBS2 (and possibly other BBSs) are able to enter the nucleus and interact with
the chromatin remodeler RNF2 regulating its protein levels and thus the transcription of its target genes. BBSs proteins such as BBS7 might regulate RNF2 levels by affecting
its availability for proteasome-mediated degradation, a possibility that needs to be tested.

strategy in the regulation of several signaling pathways including
Hedgehog, canonical Wnt, Notch and NFjB. Interestingly, the cen-
trosome/pericentriolar region is highly enriched in proteasome and
associated regulatory proteins [91]. It was observed that several
BBS proteins (1, 2, 4, 6, 7 and 8, but not 10 or 5) are able to interact
with different proteasomal subunits [90,92]. Decreased levels of
BBS1, BBS4 and oral-facial-digital syndrome-1 (OFD1, another cen-
trosomal protein) alter proteasomal subunit composition and con-
sequently inhibit its activity, as shown by increased levels of
proteins that are normally processed by the complex (Gli2, Gli3,
Notch) [92]. Interestingly, this role of the BBS proteins could be
independent of the cilium since the NFjB pathway, which does
not use the cilium but it is regulated by the proteasome, is affected
by decreased levels of BBS4 and OFD-1 (Fig. 3B; [92]).
BBS11 is an E3-ubiquitin ligase whose relationship with the cil-
ium is still poorly understood. It was proposed that BBS2 instability
when the protein is not part of the BBSome might be due to ubiq-
uitination by BBS11 and proteasomal degradation [52]. More
recently it was described that BBS11 interacts with NPHP7, a tran-
scriptional repressor associated with NPHP. However, contrarily to
what was expected BBS11 is responsible for the accumulation of
polyubiquitylated NPHP7 species, a modification that prolonged
the half-life of NPHP7 and also altered its sub-nuclear localization
and transcriptional activity. Thus, the authors propose that this
interaction may help explain the phenotypic similarities between
these two ciliopathies [93]. It was reported that BBS11/TRIM32
can ubiquitinate actin and downregulate its levels upon overex-
pression in Hek293 cells [94], findings that might be relevant to
link this protein with ciliogenesis as we will discuss next.
4.3. Actin cytoskeleton dynamics
Several studies have shown that ciliogenesis is critically depen-
dent on actin cytoskeleton dynamics. In particular, actin polymer-
ization inhibits cilia assembly [95]. Interestingly, BBS4, BBS6 and
BBS8 regulate actin polymerization. When these proteins are
absent or their levels diminished the actin cytoskeleton is reorga-
nized, increasing the amount of focal adhesions where BBS8 and
BBS9 colocalize with vinculin. These changes in actin organization
do not involve cortical actin and were ascribed to changes in RhoA
activity [96,97]. Importantly, inhibitors of RhoA activity recovered
the number of ciliated cells and cilia length in BBS4 / and BBS6 /
cells, and rescued several of the ciliopathy-associated phenotypes
observed in zebrafish treated with morpholinos against bbs8 [96].
These results suggest that BBS proteins might be involved in cilio-
genesis not only through the BBSome but also through regulation

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j.febslet.2015.07.031
8 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx
of RhoA and actin polymerization (Fig. 3C). This latter effect could
also affect other cellular activities that depend on actin dynamics,
such as cell migration or cytokinesis thus potentially expanding
the range of cellular effects of disrupting the function of the BBS
proteins.
4.4. Regulation of gene expression
Primary cilia are essential for the transduction of several signal-
ing pathways where the end result is changes in gene expression.
We have reported that BBS proteins regulate gene transcription
through a mechanism that could be independent of the cilium
and that could also involve regulation of proteasome-mediated
degradation (Fig. 3D; [98]). We observed that BBS1, 2, 4, 5, 6, 7, 8
and 10 interact with RNF2, a chromatin remodeler of the polycomb
group. Knockdown of BBS1, BBS2, BBS4 or BBS7 result in increased
RNF2 protein levels which, at least for BBS4 and BBS7 knockdowns,
translate into changes in the expression levels of several
RNF2-target genes [98]. RNF2 is a nuclear protein and importantly,
the interaction with BBS7 may occur in this compartment as we
showed that BBS7 is able to enter the nucleus from where it is
actively exported via a nuclear export signal (NES) in its primary
sequence. This active shuttling of BBS7 between the nucleus and
cytoplasm might be linked to its capacity to regulate the
proteasome-mediated processing of RNF2 and possibly other tar-
gets (Fig. 3D). Interestingly, NES motifs were also identified in
the other BBS proteins, though their functionality was not evalu-
ated. These results suggest that the capacity to enter the nucleus
and to function in that compartment might be shared by other
BBS proteins, a possibility that will need to be tested.
5. Understanding the cellular basis of the BBS phenotypes
A large body of work has shown that cilia are hubs for sensing
and transducing different signaling pathways. Coupled to this com-
plex biological function, the presence of cilia in almost all cell types
in the human body explains why ciliary dysfunction can have the
pleiotropic effect that characterize the ciliopathies. Importantly,
we now recognize a number of phenotypes as hallmarks of ciliary
dysfunction that are present to varying degrees in the different cil-
iopathies including cystic kidney disease, retinal degeneration,
obesity, polydactyly, central nervous system (CNS) malformations,
left–right asymmetry defects and others [4,7,8,33]. Importantly,
major advances have been achieved in understanding the role of
primary cilia in the etiology of these phenotypes, a matter that
has been reviewed extensively in the last years [4,5,8,33,99–101].
Therefore, just the realization that a disorder, in this case BBS, is
a ciliopathy represents a critical entry-point to start understanding
the cellular and molecular basis of the different phenotypes that
characterize the syndrome. However, there can be substantial dif-
ferences in the presentation of a given phenotype among different
clinical entities highlighting the need to understand specific func-
tions, both ciliary and extra-ciliary, of the different ciliopathy asso-
ciated proteins. Here we will briefly review how defects in the BBS
proteins are thought to explain BBS characteristic phenotypes such
as renal disease, retinal dystrophy, polydactyly, CNS defects, and
finally obesity where recent studies on BBS are providing impor-
tant insights.
5.1. Renal disease
A critical link between primary cilia and the pathogenesis of
cystic diseases of the kidney (CDKs) was initially provided by the
characterization of the Oak Ridge polycystic kidney (orpk) mouse,
a model of autosomal recessive polycystic kidney disease
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j.febslet.2015.07.031
(ARPKD), caused by a mutation in Tg737, the gene encoding a core
protein in intraflagellar transport: IFT88/Polaris ([102] and refer-
ences within). Subsequent studies in a number of CDK models,
including BBS, have led to the realization that cilia in the epithe-
lium of the renal tubules play a critical role maintaining the home-
ostasis of the tissue, to the extent of now considering that likely all
forms of CDKs are linked to cilia dysfunction [103,104].
Although the renal aspect of the disease has been difficult to
reproduce in different BBS models, especially mice, the study of
the BBS proteins has contributed to understanding the cellular
basis of CDKs. The Wnt signaling pathway plays an important role
for both the development and maintenance of the kidney.
Depletion of BBS proteins results in Wnt signaling defects whereby
canonical b-catenin dependent signaling is upregulated at the
expense of a reduction in the non-canonical planar cell polarity
(PCP) pathway [90,105]. Importantly, both upregulated canonical
Wnt signaling and defective PCP have been shown to promote cys-
togenesis (reviewed in [106]). In addition, the BBS proteins have
been shown to participate in Shh signaling transduction, a cascade
that also plays a role in renal cystogenesis [12,66,107].
In addition to modulating signaling cascades relevant to the
pathogenesis of CDKs, some BBS proteins interact with PC1 and
PC2, the two major proteins affected in autosomal dominant poly-
cystic kidney disease (ADPKD). PC1 and PC2 form a channel that
localizes to the ciliary membrane and in the epithelium lining
the renal tubules participate in sensing and transducing fluid flow
shear stress into Ca2+ signaling to control cell proliferation and dif-
ferentiation [108]. Four members of the BBSome (BBS1, BBS4, BBS5
and BBS8) physically interact with PC1 but depletion of only BBS1
and BBS3 result in defective ciliary targeting of PC1, data that fur-
ther supports the notion that different BBS proteins have specific
functions [109]. In line with these observations, depletion of
BBS7 does not affect the ciliary localization of PC1 and PC2 but
affects that of dopamine D1 receptor [72]. The BBSome, or at least
some BBS proteins, appear to also play a role mediating the ciliary
targeting of PC2 since expression of a dominant negative form of
Rab8a results in mislocalization of PC2 [110]. Importantly, muta-
tions in the Paramecium BBS orthologs also result in PKD2 loss from
cilia [111]. Finally, it was reported recently that bbs-4 and bbs-5
act together to regulate the ciliary exit and lysosomal degradation
of PC2 and other ciliary receptors in C. elegans [112]. Therefore, the
renal phenotype in BBS could be caused by a combination of signal-
ing defects involving canonical Wnt, PCP, Shh and PC1/PC2 medi-
ated Ca2+ signaling.
5.2. Retinal degeneration
Retinal degeneration has been associated with impaired
IFT-mediated transport across the connecting cilium (CC), a highly
modified cilium linking the photoreceptor inner and outer seg-
ments [113,114]. The BBS proteins play a role transporting rhodop-
sin to the base of the CC and defective IFT has been shown to cause
retinal degeneration in several mutants [33,50]. Therefore, retinal
degeneration in BBS is thought to involve a defect in transport of
specific cargo proteins to the base of the CC and defects in
IFT-mediated transport across the CC. However, while these mech-
anisms are likely relevant and possibly represent the main activity
of the BBS proteins in the retina, restricting the activity of this
group of proteins to a transport-based model might be an oversim-
plification since several of the ‘‘non-ciliary’’ activities of the BBS
proteins could also contribute to photoreceptor degeneration. For
example, the documented perturbations in actin dynamics, gene
expression and proteasome activity resulting from BBS malfunc-
tion could also play a significant role in the development of this
phenotype, a possibility that will have to be addressed.
 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx
5.3. Polydactyly
Hedgehog signaling in vertebrates is heavily dependent on the
primary cilium whereby all the proteins that participate in the
transduction of the pathway are localized to the cilium and their
localization changes upon binding of Shh to its receptor Ptch1
(Fig. 1A). The effectors of the pathway, the Gli transcription factors,
also enter the ciliary compartment and their processing and
activation occurs inside the organelle [6,115]. Shh signaling con-
trols patterning in the limbs and therefore defects in this signaling
cascade can be reconciled with defects in digit number and identity
[6].
The BBS proteins participate in Shh signal transduction and
BBS1 directly interacts with Ptch1 and Smo [66]. In zebrafish, fin
bud patterning is affected by misexpression of different bbs genes
causing altered Shh signaling [116]. Interestingly, in BBS the poly-
dactyly is postaxial which led to the suggestion that a combination
of defects in Shh and other signaling pathways, primarily Wnt,
could be contributing to this phenotype in this ciliopathy [33].
5.4. Central nervous system
BBS is characterized by learning difficulties, mental retardation,
behavioral defects and other CNS defects [1,117]. The presence of
cilia in different neuronal cell types has been known for decades
but the importance of this organelle in different aspect of neuronal
biology has been realized only recently and it is an area of intense
research. The role of the cilium in the transduction of key signaling
pathways such as Wnt and Shh is undoubtedly relevant to under-
stand their function in neurons but cilia are being shown to play
additional roles. For example, conditional ablation of cilia has been
shown to result in disrupted dendritic arborization and the estab-
lishment of neuronal networks [118]. In addition, cilia are being
shown to participate in diverse aspects of neuronal biology such
as maintenance of progenitor pools, neurogenesis and neuronal
migration, findings that will promote a better understanding of
the cellular basis of the different CNS defects that characterize
BBS and other ciliopathies (for thorough reviews on the role of cilia
in the CNS see [119,120]).
5.5. Obesity in BBS
Since the initial link between BBS protein function and cilia two
major hypotheses have been considered to explain the obesity
aspect of the phenotype. The first model was developed centered
on a hypothalamic/neuro-endocrine dysfunction where cilia in
specific areas of the brain play a critical role regulating signaling
cascades that affect feeding and satiety. On the other hand, more
recent data support a role for the BBS proteins and cilia in main-
taining the homeostasis of peripheral tissues (revised in
[121,122]).
5.5.1. A neuroendocrine origin for obesity in BBS
Specific loss of cilia in hypothalamic POMC neurons causes obe-
sity, hyperphagia and elevated serum insulin levels, glucose and
leptin, an anorexigenic hormone critical in weight regulation
[123]. Therefore, it was initially hypothesized that the obesity in
BBS could be primarily due to defects in ciliary function in the
CNS. Bbs2 / , Bbs4 / , Bbs6 / , and Bbs1M390R/M390R mice develop
obesity associated with an accumulation of abdominal fat,
decreased locomotion activity and hyperphagia [73–76]. These ani-
mals present increased serum leptin levels and leptin resistance
and it was shown that the BBS proteins physically interact with
the leptin receptor and mediate its traffic, thus potentially explain-
ing the leptin phenotype [21,124].
Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031
9
However, while leptin resistance is observed in different Bbs
mouse models, it is not yet clear whether it is the main driver lead-
ing to obesity or a consequence of it. In the Bbs mice mentioned
above, leptin resistance preceded the onset of obesity, suggesting
that alterations in the leptin-signaling axis could drive the
increased in body weight [21]. However, it has been proposed that
leptin resistance could be a secondary consequence to the increase
in body weight and also that cilia may not be directly involved in
leptin responses [125]. Using an inducible system, Berbari and col-
leagues targeted Ift88 in 8 week old mice to then assess body
weight gain and the response to leptin stimulation. Upon inducing
the mutation, an initial phase of 3 weeks where knockout and wild
type littermates maintained a normal body weight was followed
by the development of obesity at 3 months in Ift88 / animals.
Importantly, obese Ift88 / animals then were shown to respond
to caloric restriction reducing their body weight to that of controls.
Therefore, the authors were able to assess leptin response in ani-
mals lacking cilia in hypothalamic neurons and in three different
body weight contexts: lean, obese, and lean after being obese.
Leptin administration in pre-obese, but cilia deficient Ift88 / mice,
resulted in activation of the leptin cascade as measured by a reduc-
tion in food intake and phosphorylation of STAT3 showing that in
the absence of cilia animals can still respond to leptin. When
Ift88 / mice were obese, leptin administration did not have any
effect of feeding behavior or pathway activation. Finally, in
Ift88 / mice that regained normal body weight values after diet,
the authors observed a reduction in leptin levels and a response
to leptin administration. Overall, these data show that at least in
this experimental setup, leptin resistance is a consequence rather
than the driver of obesity [125]. Functional differences between
the BBS proteins and IFT88 could certainly explain these seemingly
contradictory results. More difficult to reconcile however is the fact
that in the Berbari et al. study, pre-obese Bbs4 / mice did not pre-
sent increased leptin levels and responded to exogenous leptin
administration [125]. Differences in the genetic background of
mice or in the experimental setup could account for the observed
discrepancies. Importantly, these results might be indicating that
while leptin signaling defects do play an important role in the
development of obesity in BBS and other ciliopathies, mechanisms
that are still unknown might be important to initiate the process.
Interestingly, the functional relationship between leptin and cilia
appears to be even more complex as a recent work reports on lep-
tin regulating cilia assembly and ciliary length by destabilizing
actin filaments and increasing intraflagellar transport proteins
through gene transcription regulation [126,127]. Therefore, leptin
could modulate cilia length and the sensitivity of hypothalamic
neuronal cilia to metabolic signals.
Another important CNS defect in BBS is the mislocalization of G
protein coupled receptors (GPCRs) involved in the regulation of
feeding behavior. Both Sstr3 and Mhcr1 are receptors localized in
neuronal cilia involved in feeding satiety, and their localization
and function is altered upon disruption of BBS proteins [49,128].
In addition, a recent localization screen of GPCRs in neuronal cilia
identified seven receptors including the neuropeptide Y receptor
(NPY2R), another important anorexigenic pathway [129].
Depletion of the BBSome subunit BBIP10 in RPE cells result in
decreased ciliary localization of NPY2R, Bbip10 / mice do not pre-
sent NPY2R in hypothalamic neuronal cilia, and mutant animals do
not respond to anorexigenic NPY2R-based stimuli [129]. In addi-
tion to GPCRs, the BBS proteins participate in the intracellular traf-
fic of other receptors that are likely relevant to understand
neuronal signaling and disease pathogenesis. BBS4 regulates the
cilia localization of the brain derived neurotrophic factor (BDNF)
receptor, TrkB, and its mislocalization upon depletion of BBS4
results in impaired BDNF mediated signaling, a pathway involved
in controlling feeding behavior [130]. Therefore, mislocalization
10 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx
and defective signaling of GPCRs and other relevant signaling path-
ways are likely contributors to the altered feeding behavior and
obesity in BBS.
5.5.2. Adipogenesis defects in the etiology of the BBS related obesity
Besides a defect in hypothalamic ciliated neurons, adipocyte
differentiation and misregulation of adipose tissue homeostasis
are proving to be important aspects in the development of
BBS-associated obesity. First it was realized that the BBS genes
change their expression pattern during adipogenesis [131]. In addi-
tion, it was shown that while cilia are present in differentiating
pre-adipocytes, cilia are lost during differentiation and mature adi-
pocytes are non-ciliated cells [132]. Albeit transient, the presence
of a primary cilium during adipocyte differentiation appears to
be important since mesenchymal stem cells (MSCs) require the
presence of primary cilia to differentiate toward the adipogenic
lineage [133]. Moreover, Wnt and Hedgehog receptors, pathways
known to regulate adipogenesis, are present in these transient cilia
of differentiating pre-adipocytes [132].
Therefore cilia reabsorption or cilia dysfunction promoted by
defects in the BBS proteins could affect the rate of adipogenesis.
In this context, it was shown that blocking BBS10 and BBS12 leads
to defective ciliogenesis and exacerbated adipogenesis promoted
by the activation of the proadipogenic pathways GSK3 and
PPARc [132]. More recently, BBS4 was shown also to affect prolif-
eration and differentiation of adipocytes [134]. However, the effect
on adipogenesis varies depending on the specific ciliary protein
being affected. In contrast to BBS10 and BBS12, knockdown of
ALMS1 (mutated in ALMS) in 3T3-L1 inhibited adipogenesis
[135]. Depletion of the ciliary proteins Pkd1 and BBS12 also
resulted in enhanced adipogenesis while inhibition of the IFT
anterograde molecular motor Kif3a impaired adipocyte differenti-
ation [136,137].
Therefore, albeit the primary cilium plays a critical role mediat-
ing adipocyte differentiation, the identity of the affected protein
and thus the specific way in which its absence affect ciliary and/or
non-ciliary functions associated with adipogenesis is likely to
explain important differences in the presentation of obesity.
Obesity is commonly associated with the development of insulin
resistance and type 2 diabetes (T2D). However, a study comparing
BBS patients with BMI-matched controls showed that the former
present better glucose tolerance, thus hinting at potentially impor-
tant differences between BBS-related and common obesity [138].
Marion and colleagues showed that knockdown of BBS12 in
hMSCs results in increased adipogenesis that is accompanied by
increased expression of the insulin receptor (IR) and GLUT4,
increased localization of GLUT4 to the plasma membrane, and
overall increased glucose absorption, and Bbs12 / animals present
increased insulin sensitivity, improved glucose metabolism and
reduced inflammation [136]. Importantly, since adipocytes secrete
leptin in response to insulin and glucose, the increased glucose
absorption and the overall increased adipogenesis are likely to con-
tribute to the hyperleptinemia that characterize BBS [21,138]. In
contrast, Gerdes et al. have uncovered a critical role for cilia and
BBS4 in pancreatic b-cell function whereby the insulin receptor is
found on cilia upon stimulation, and Bbs4 / mice show impaired
insulin secretion and signaling [139]. Altogether, these data is
showing that obesity in BBS likely has multiple contributing factors
where a CNS defect leading to hyperphagia, a peripheral tissue
defect leading to altered adipogenesis and impaired b-cell function
are likely to be contributing factors. Finally, the discrepancies
between different BBS models again highlight the importance of
understanding the specific functions of individual BBS proteins.
Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031
6. Concluding remarks
Since the cloning of the first BBS genes an impressive amount of
work has followed, both regarding the genetics and deciphering
the function of the BBS proteins. The studies in BBS have been
instrumental in shaping the concept of ciliopathies, which today
encompasses a number of disorders and syndromes that were,
not long ago, considered completely disconnected. In addition,
we now recognize a set of phenotypes that are considered typical
consequences of cilia dysfunction, findings that have facilitated
the classification of additional human conditions as ciliopathies
and have therefore catalyze the identification and initial functional
characterization of causal genes.
The identification of the BBSome was a milestone to understand
the role of the BBS proteins in cilia biology and to start dissecting
the cellular basis of the syndrome. In this context, the possibility of
the BBSome presenting different intermediate complexes/isoforms
is intriguing and raises questions both from a genetic and a cellular
perspective [52]. Are there different BBSome complexes that could
achieve different functions? Can mutations in patients affect the
balance between BBSome complexes? In this scenario, the levels
and balance of different BBSome ‘‘isoforms’’ could be affected in
different ways by mutations found in patients and thus could con-
tribute to disease phenotypic variability. Further work will be
required to address these questions.
Finally, an increasing body of data is demonstrating that at least
some of the BBS proteins are likely not functionally restricted to
the primary cilium, a factor that could explain why BBS is one of
the most pleiotropic ciliopathies and also that could be relevant
to fully understand the etiology of the syndrome. A more general-
ized role in intracellular transport is an example of this since the
effect of disrupting the BBS proteins might affect trafficking of pro-
teins destined to other regions of the plasma membrane, to a given
organelle, or that depend on the endosomal and secretory path-
ways for their function as it has been shown for Notch [83]. The
possible shuttling of BBS proteins in and out of the nucleus pro-
vides another means by which these proteins could modulate sig-
naling for example. The regulation of proteasome-mediated
degradation of important signaling moieties also provides critical
insight to understand the etiology of BBS. Identifying target pro-
teins and establishing whether this role depends or its linked to cil-
iary function are key aspects to understand this function.
Dissecting cilia versus non-ciliary functions of the BBS proteins will
be challenging but studying the function of BBS proteins in
non-ciliated cells could provide important insight. An example
could be studying the role of the BBS proteins on the
proteasome-mediated degradation of NFkB in non-ciliated cells
such as lymphocytes. Importantly, understanding the different
functions of the BBS proteins will not only allow us to fully under-
stand the cellular basis of this condition but will likely provide
novel entry-points for improving patient diagnosis, management,
and for the rational design of therapeutic interventions.
Acknowledgments
We apologize to all the researchers whose original contribution
was not properly cited. This work was supported by ANII-Innova
and FOCEM (MERCOSUR Structural Convergence Fund). R.N. and
M.C.-R. were supported with scholarships from the ‘‘Agencia
Nacional de Investigación e Innovación (ANII, Uruguay)’’ and
‘‘Comisión Académica de Posgrado, Universidad de la República,
Uruguay’’. J.L.B., M.C.-R. and F.I. are supported by ANII and J.L.B.
and F.I. are researcher from the Programa para el Desarrollo de
las Ciencias Básicas (PEDECIBA, Uruguay).
 R. Novas et al. / FEBS Letters xxx (2015) xxx–xxx 11

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Please cite this article in press as: Novas, R., et al. Bardet–Biedl syndrome: Is it only cilia dysfunction?. FEBS Lett. (2015), http://dx.doi.org/10.1016/
j.febslet.2015.07.031