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Ciliary biology Understanding the cellular and genetic basis of human ciliopathies.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 151C:263 – 280 (2009)
Ciliary Biology: Understanding the Cellular and Genetic
Basis of Human Ciliopathies
Motile cilia have long been known to play a role in processes such as cell locomotion and fluid movement whereas
the functions of primary cilia have remained obscure until recent years. To date, ciliary dysfunction has been
shown to be causally linked to a number of clinical manifestations that characterize the group of human disorders
known as ciliopathies. This classification reflects a common or shared cellular basis and implies that it is possible to
associate a series of different human conditions with ciliary dysfunction, which allows gaining insight into
the cellular defect in disorders of unknown etiology solely based on phenotypic observations. Furthermore,
to date we know that the cilium participates in a number of biological processes ranging from chemo- and
mechanosensation to the transduction of a growing list of paracrine signaling cascades that are critical for the
development and maintenance of different tissues and organs. Consequently, the primary cilium has been
identified as a key structure necessary to regulate and maintain cellular and tissue homeostasis and thus its study is
providing significant information to understand the pathogenesis of the different phenotypes that characterize
these human conditions. Finally, the similarities between different ciliopathies at the phenotypic level are proving
to be due to their shared cellular defect and also their common genetic basis. To this end, recent studies are
showing that mutations in a given ciliary gene often appear involved in the pathogenesis of more than one clinical
entity, complicating their genetic dissection, and hindering our ability to generate accurate genotype–phenotype
correlations. ß 2009 Wiley-Liss, Inc.
KEY WORDS: cilia; cystic kidney disease; retinal dystrophy; polydactyly; obesity; Wnt; Shh; PDGF
How to cite this article: Cardenas-Rodriguez M, Badano JL. 2009. Ciliary biology: Understanding the
cellular and genetic basis of human ciliopathies. Am J Med Genet Part C Semin Med Genet 151C:263–280.
Cilia are evolutionary conserved organelles that have been recognized for more
than a 100 years [Zimmermann, 1898].
These antenna-like structures can be
classified in two main types according to
their ultrastructure and their capacity
to move: motile and immotile/primary
cilia. While cilia immotility has long
been associated with distinct clinical
manifestations, it has been only recently
realized the role that the primary cilium
is playing in the pathogenesis of several
human conditions. Consistent with their
broad cellular distribution, their evolutionary conservation, and their emerging role in the transduction of important
paracrine signaling pathways, perturbations in the function of primary cilia are
being implicated in a wide spectrum of
human diseases: the ciliopathies. This
classification includes a number of disorders that range from polycystic kidney
disease (PKD) and nephronophthisis to
broad pleiotropic syndromes [Badano
et al., 2006b; Sharma et al., 2008]. Here
we review the basic biology of cilia
and the multiple roles that have been
ascribed to these organelles to highlight
how this knowledge is shedding light
into our understanding of the cellular
and genetic basis of this group of human
Structure and Classification
Magdalena Cardenas-Rodriguez (MSc) is a Ph.D. student in the ‘‘Program for the development
of basic sciences’’ (PEDECIBA) from the Universidad de la Republica, Uruguay. She is conducting
her thesis work in Dr. Badano’s laboratory working on the functional characterization of BBS and
BBS modifier proteins.
Dr. Jose L. Badano holds a faculty position at the Institut Pasteur of Montevideo, Uruguay. He
received his Ph.D. from the Department of Molecular and Human Genetics at Baylor College of
Medicine, Houston, TX and performed his post-doctoral training with Dr. Nicholas Katsanis at
Johns Hopkins University, Baltimore, MD, where he continued his work on Bardet-Biedl syndrome
and other ciliopathies
Grant sponsor: Genzyme Renal Innovations Program (GRIP); Grant sponsor: Agencia Nacional
de Investigación e Innovación (ANII); Grant sponsor: Programa de Apoyo Sectorial a la Estrategia
Nacional de Innovación - INNOVA URUGUAY; Grant number: DCI-ALA/2007/19.040.
*Correspondence to: Jose L. Badano, Institut Pasteur de Montevideo, Mataojo 2020,
Montevideo CP 11400, Uruguay. E-mail:
Received 15 June 2009; Accepted 14 September 2009
DOI 10.1002/ajmg.c.30227
Published online 27 October 2009 in Wiley InterScience(
ß 2009 Wiley-Liss, Inc.
Cilia and flagella extend from the cellular
membrane of non-proliferating cells
and are composed of a microtubule
axoneme that emanates from a basal
body, a structure composed of nine
microtubule triplets that derives from
the mother centriole of the centrosome
[Rosenbaum and Witman, 2002]. In
general, motile cilia axonemes are composed of nine outer microtubule doublets surrounding a central pair in a 9 þ 2
configuration. Inner and outer dynein
arms are responsible for generating force
IFT particle
Cytoplasmic dynein
Retrograde IFT
Anterograde IFT
Outer dynein arm
Inner dynein arm
Radial spoke
Ciliogenesis and
cell cycle
Transition fibers
Basal Body
Figure 1. Basic ciliary structure. A: Schematic representation of a cilium and cross-section of a basal body composed of microtubule
triplets and a ‘‘9 þ 2’’ and a ‘‘9 þ 0’’ axoneme showing the position of dynein arms and radial spokes needed for force generation and
coordination. Along the outer microtubule doublets of the axoneme, molecular motors transport IFT particles. B: Ciliogenesis is tightly
linked to cell cycle progression occurring in G1/G0. Mouse kidney cells (IMCD3) are shown where g- and acetylated tubulin have been
stained in green showing centrioles and the axoneme. DAPI has been used to stain DNA.
whereas radial spokes regulate the direction of ciliary beating. Primary cilia
generally lack the central pair of microtubules (9 þ 0 configuration) and the
inner dynein arms (Fig. 1A). However,
this classification is simplistic and motile
9 þ 0 and immotile 9 þ 2 cilia can
be found. For example, 9 þ 0 cilia in
the embryonic node move in a vortical
fashion to generate extra-embryonic
fluid flow (see below) and the immotile
kinocilium in the inner ear has a 9 þ 2
Since protein synthesis does not
occur inside cilia, cells have developed a
specialized mechanism named intraflagellar transport (IFT), first described in
the flagellated single-celled green algae
Chlamydomonas reinhardtii, necessary for
the formation, maintenance and function of cilia [Kozminski et al., 1993].
Since protein synthesis does
not occur inside cilia, cells
have developed a specialized
mechanism named
intraflagellar transport (IFT),
first described in the flagellated
single-celled green algae
Chlamydomonas reinhardtii,
necessary for the formation,
maintenance and function
of cilia
IFT requires the coordinated action
of structural, adaptor, and molecular
motors to move IFT particles in and
out of the cilium (anterograde and
retrograde movement, respectively).
Anterograde movement is achieved
through kinesin-II, a heterotrimeric
complex formed by two motor subunits,
KIF3A and KIF3B in vertebrates, and a
non-motor subunit called KAP. Interestingly, it has been shown that other
kinesins can also participate in the
process although their exact role needs
to be determined. The molecular motor
responsible for retrograde transport is
cytoplasmic dynein 2, which in turn is
composed of heavy, intermediate and
light chains [Fig. 1A; for an in depth
review of IFT see Rosenbaum and
Witman, 2002; Pedersen and Rosenbaum, 2008].
IFT is critical to maintain the functionality of cilia and thus its disruption
or impairment is causally linked to
different human phenotypes and conditions that will be discussed in
following sections. One particular cell
type that heavily depends on intact IFT is
the photoreceptor and consequently,
retinal degeneration is a characteristic
phenotypic outcome of ciliary dysfunction [Table I; for an in depth review see
Insinna and Besharse, 2008]. The outer
segment of the photoreceptors derives
from the plasma membrane of a modified primary cilium that also connects
it with the inner segment. Therefore,
both the formation and maintenance
of the photoreceptor outer segment
requires IFT and defects in this process
result in photoreceptor cell death and
retinal degeneration in a manner that
is proportional to the disruption in
IFT. For example, mutations in the
IFT proteins IFT88 or IFT57 which
abrogate or reduce IFT respectively,
result in either lost or short outer
segments [Pazour et al., 2002a; Krock
and Perkins, 2008]. Similarly, conditional depletion of Kif3a in photoreceptors results in the accumulation
of proteins normally transported into
the outer segment, such as opsin and
arrestin, leading to cell death [Marszalek
et al., 2000].
TABLE I. Principal Phenotypes Observed in the Ciliopathies
CNS malformations
Cystic kidney
Gonadal malformations
Heart disease
Hepatic dysfunction
Mental retardation/Developmental delay
Pulmonary dysfunction
Retinal degeneration
Left–right asymmetry defects
Skeletal defects
PKD, polycystic kidney disease; NPHP, nephronophthisis; MKKS, McKusick–Kaufman syndrome; SLSN, Senior–Løken syndrome;
EVC, Ellis-van Creveld; JATD, Jeune asphyxiating thoracic dystrophy; OFD, orofaciodigital syndrome; ALMS, Alström syndrome; JS,
Joubert syndrome/Cerebello-oculo-renal syndrome; BBS, Bardet–Biedl syndrome; MKS, Meckel–Gruber syndrome; CNS, Central
nervous system.
Ciliogenesis and Cell Cycle
Cilia are post-mitotic structures that
are present while cells are in G0/G1
and the beginning of the S phase, before
the centrioles are needed to organize the
mitotic spindle (Fig. 1B). Importantly,
the tight link between cilia formation/
disassembly and cell cycle progression
not only relies in the availability of
centrioles but also is supported by the
specific activity of centrosomal proteins
participating in the control of ciliogenesis [reviewed by Santos and Reiter,
Cilia are post-mitotic
structures that are present while
cells are in G0/G1 and the
beginning of the S phase, before
the centrioles are needed to
organize the mitotic spindle
(Fig. 1B). Importantly,
the tight link between cilia
formation/disassembly and cell
cycle progression not only relies
in the availability of centrioles
but also is supported by the
specific activity of centrosomal
proteins participating in the
control of ciliogenesis
2008]. For example, CP110 is a protein
involved in centrosome duplication and
cytokinesis that has been shown to
inhibit ciliogenesis through an interaction with Cep97 and CEP290, a protein
that is mutated in several ciliopathies
[Table II; Spektor et al., 2007; Tsang
et al., 2008]. Depletion of either Cep97
or CP110 uncouples the ciliary cycle and
cell division leading to the formation of
cilia in proliferating cells while overexpression of CP110 in serum-starved
cells inhibits ciliogenesis [Spektor et al.,
Cells generally reabsorb the cilium
in order to divide and thus the disassembly of cilia is also tightly regulated.
Aurora A (AurA), a centrosomal protein
involved in the regulation of mitotic
entry, has been shown to interact with
the focal adhesion scaffolding protein
HEF1, to facilitate ciliary disassembly by
promoting deacetylation of axonemal
tubulin through the histone deacetylase
HDAC6 [Pugacheva et al., 2007].
Another example is the family of
NIMA-related protein kinases (Nrks or
Neks) which have been postulated to
play a role in the coordination between
cell cycle and cilia [Parker et al., 2007].
Importantly, mutations in Nek1 and
Nek8 are responsible for two mouse
models of cystic kidney disease, a hallmark feature of ciliary dysfunction
[Table I; Upadhya et al., 2000; Liu
et al., 2002].
As we will discuss in following
sections, cilia can regulate cell proliferation through the modulation of different signaling cascades. In addition,
several ciliary proteins appear to directly
affect cell proliferation through putative
extraciliary roles. For example, depletion of IFT27 in Chlamydomonas results
in the expected loss of flagella but also
cytokinesis defects [Qin et al., 2007]. In
mammalian cell lines, overexpression of
IFT88, which remains associated with
the centrosome through the cell cycle,
leads to cell cycle arrest regulating
the G1–S transition. Furthermore,
it has been shown that IFT88 inhibits
the RNA polymerase II binding
protein Che1 which is no longer able
to suppress retinoblastoma (Rb), a
TABLE II. List of Selected Ciliary Genes/Proteins and Their Link to Ciliopathies
Functional information
Basal body/cilia, cell–cell junctions. Regulate ciliary access
Centrosomes/basal body/cilia, cell–cell junctions.
Involved in Wnt signalling
Cilia. Suggested role in Wnt signaling
Centrosomes/basal body/cilia, also actin cytoskeleton
Primary cilia in renal tubular epithelial cells and retinal cells
Centrosome/basal body/cilia; ciliogenesis
Possible role in Shh signalling
Basal bodies; possible role in Shh signalling
Cell cycle regulation
Chondrocyte cilia; involved in Hh signaling
Basal body/axoneme; IFT particle. Possible role in Shh
Centrosome/basal body; IFT and intracellular transport
Centrosome/basal body
Member of the Ras superfamily of small GTP-binding
proteins; possible role in ciliary transport
Centrosome/basal body. Pericentriolar organization
Basal body; possible role in ciliogenesis
Centrosome/basal body; group II chaperonin-like protein;
possible role in cell cycle
Basal body; possible role in IFT
Centrosome/basal body; possible role in IFT
Possible role in adipogenesis
Group II chaperonin-like protein
Similar to E3 ubiquitin ligase; possible role in proteasome
Group II chaperonin-like protein
Centrosome/basal body; ciliogenesis
Cilia and plasma membrane in ciliated cell-lines; ciliogenesis
Basal body, ciliogenesis
Centrosome/basal body/cilia; cell–cell junctions
Centrosome/basal body; ciliary assembly
Centrosome/basal body. Implicated in left–right axis
specification and CE movements
Formation of distal/subdistal appendages of mother
centrioles and ciliogenesis
BBS, MKS-like
BBS, MKS-like
NPHP, nephronophthisis; MKKS, McKusick–Kaufman syndrome; SLSN, Senior–Løken syndrome; EVC, Ellis-van Creveld; JATD, Jeune
asphyxiating thoracic dystrophy; OFD, orofaciodigital syndrome; ALMS, Alström syndrome; JS, Joubert syndrome; BBS, Bardet–Biedl
syndrome; MKS, Meckel–Gruber syndrome; CE, convergence and extension; IFT, intraflagellar transport; Hh, hedgehog; Shh, sonic
negative regulator of the cell cycle
[Robert et al., 2007]. Interestingly,
ciliary dysfunction in vivo does not seem
to result in marked cell proliferation
defects nor it is associated with oncogenic phenotypes suggesting that there
is redundancy in the system and cell
cycle checkpoints are not largely
Motile Cilia Dysfunction: Primary
Ciliary Dyskinesia, Hydrocephalus
and Left–Right Determination
Ciliary immotility in the respiratory
tract and the sperm flagellum has long
been associated with a defined set of
human phenotypes. Afzelius [1976]
observed cilia lacking dynein arms in
patients with immotile sperm and respiratory problems, characteristic phenotypes in patients with primary ciliary
dyskinesia (PCD, OMIM 244400)
[Afzelius, 1976]. To date we know that
mutations in either of several genes
encoding different components of the
highly complex machinery required to
generate and coordinate ciliary movement, can cause this condition (Fig. 1A).
For example, mutations in genes encoding for dynein intermediate and heavy
chains, such as DNAI1, DNAH5, and
DNAH11, and other structural ciliary
defects have been found in PCD patients
[Pennarun et al., 1999; Bartoloni et al.,
2002; Olbrich et al., 2002; Sharma
et al., 2008]. While sinusitis, infertility
and bronchiectasis were, to a degree,
expected consequences from ciliary
immotility in heavily ciliated tissues,
the cellular basis of hydrocephalus, a
condition also affecting PCD patients,
was not fully understood. Interestingly, it
is now known that ciliary beating in the
ependymal cells lining the brain ventricles generates a flow of cerebrospinal
fluid that is necessary to maintain an
open aqueduct and mutations in the
axonemal dynein heavy chain Mdnah5 in
mice result in defective ependymal flow
and hydrocephalus [Ibanez-Tallon et al.,
2004]. Furthermore, the Chlamydomonas
ortholog of Hydin, mutated in the
congenital hydrocephalus hy3 mouse, is
a component of the central pair of
microtubules that is required for motility
of the flagellum and cilia in hydin mutant
mice have been shown to present
structural axonemal defects and seriously compromised motility [Lechtreck
and Witman, 2007; Lechtreck et al.,
Another hallmark feature of ciliary
dysfunction is defective determination
of the left–right axis of symmetry
(Table I), a characteristic feature of
Kartagener syndrome (KS; OMIM
244400) which is defined by PCD and
situs inversus. In vertebrates, organs are
normally distributed asymmetrically
between the left and right (LR) side of
the body and situs inversus and heterotaxy
denote a complete reversal or partial
mis-positioning of organs, respectively.
Interestingly, it has been shown that the
first asymmetries in LR are established
through the activity of motile primary
cilia in the LR organizer: the embryonic
node in the mouse or Kupffer’s vesicle
in zebrafish for example. Using Kif3b
mutant mice Nonaka and colleagues
demonstrated that motile primary cilia
in the node are responsible for generating a leftward flow of extra-embryonic
fluid, the nodal flow, which represents
the earliest recognizable LR asymmetry
in the developing embryo [Nonaka
et al., 1998]. Furthermore, an artificially
created flow applied over mouse
embryos in culture is able to determine
the LR axis in both wild type embryos
and mutants with immotile cilia [Nonaka et al., 2002]. Additionally, mutations
in the left–right dynein (lrd) gene, in the
mouse model inversus viscerum (iv/iv),
and in the axonemal dynein heavy chain
5 (DnaHC5), result in immotile cilia and
randomization of body situs [Supp et al.,
1997; Okada et al., 1999; Olbrich et al.,
2002; McGrath et al., 2003].
Two main models of LR determination have been proposed although
neither is sufficient to satisfactorily
explain the diverse LR defects observed
in patients and animal models. The first
model postulates that the leftward flow is
sensed by mechanosensory cilia on the
right side of the node that upon bending,
initiate a Ca2þ signaling cascade that is
translated into differential gene expression of Nodal and Lefty [reviewed by
Basu and Brueckner, 2008]. Supporting
this model, it has been shown that there
are two types of primary nodal cilia: a
group of cilia localized in the center of
the node that express the axonemal
dynein lrd and can generate fluid flow
through a clockwise rotational movement and a second type of non-motile
cilia that sense the mechanical stimulus
in a process that requires polycystin-2
(PC2), a protein mutated in human
polycystic kidney disease [see below;
McGrath et al., 2003]. The second
model is based on a flow-generated
morphogen gradient that could initiate
the LR specification cascade [Okada
et al., 2005]. Interestingly, fibroblast
growth factor (FGF) signaling can
regulate the release of nodal vesicular
parcels (NVPs), membrane covered
particles that are enriched for Sonic
hedgehog and retinoic acid. These
NVPs are transported by nodal flow
and are thought to release their cargo on
the left wall of the node to initiate
signaling [Tanaka et al., 2005].
Non-Motile Primary Cilia and
Their Link to Human Disease
In contrast to motile cilia, the association
between the primary cilium and human
disease had to wait until recent years and
a key model has undoubtedly been the
Oak Ridge polycystic kidney (orpk)
In contrast to motile cilia,
the association between the
primary cilium and human
disease had to wait until
recent years and a key model
has undoubtedly been the Oak
Ridge polycystic kidney
(orpk) mouse.
mouse. Orpk mice bear a hypomorphic
allele of Tg737 which encodes
the mouse ortholog of Chlamydomonas
IFT88, a protein that localizes to basal
bodies and cilia and is involved in IFT.
Interestingly, both motile and primary
cilia in Tg737orpk animals are structurally
defective and shorter than normal cilia
while complete Tg737 nulls lack cilia
and present with neural tube problems,
LR defects and growth arrest during
embryogenesis [Moyer et al., 1994;
Yoder et al., 1995; Murcia et al., 2000;
Pazour et al., 2000; Taulman et al.,
2001]. The orpk mouse is a model of
autosomal recessive polycystic kidney
disease (ARPKD; OMIM 263200), a
condition that presents in early childhood and is characterized by renal cysts
and liver fibrosis providing a direct link
between primary cilia and human
The Role of Cilia in
the Pathogenesis of Cystic
Kidney Disease
Cystic diseases of the kidney (CDKs) are
a group of human genetic disorders
characterized by the formation of renal
cysts that range from PKD to syndromes
in which the formation of cysts in the
kidney is a feature of a broader spectrum
of clinical manifestations. A number of
mouse models and the identification of
genes causing CDKs in humans have
further supported the link between
ciliary dysfunction and cystogenesis.
For example cystin, the protein encoded
by the Cys1 gene, which is mutated in
the congenital polycystic kidney mouse
(cpk), localizes to cilia in renal epithelial
cells [Yoder et al., 2002]. Also, the
absence of cilia in the renal epithelia of
mice in which Kif3A has been conditionally targeted correlates with the
formation of renal cysts [Lin et al., 2003].
Studies in human conditions such as
autosomal dominant and recessive polycystic kidney disease (ADPKD and
ARPKD) have also supported a ciliary
role during cystogenesis. Mutations in
two genes, PKD1 and PKD2, encoding
the proteins polycystin-1 (PC1) and 2
(PC2), respectively, are the most frequent genetic alterations found in
ADPKD [Consortium TEPKD, 1994;
Mochizuki et al., 1996]. PC1 is a large
transmembrane protein that interacts
with PC2, a nonselective cation channel,
to form a Ca2þ channel that localizes to
primary cilia in the renal epithelium
[Qian et al., 1997; Tsiokas et al., 1997;
Hanaoka et al., 2000; Gonzalez-Perrett
et al., 2001; Yoder et al., 2002; Pazour
et al., 2002b]. ARPKD is caused by
mutations in PKHD1, which also encodes a ciliary protein named polyductin/
fibrocystin [Onuchic et al., 2002; Ward
et al., 2002, 2003]. Although the exact
function of polyductin/fibrocystin is still
not known, it has been suggested that it
plays a role in collecting duct cell
differentiation by interacting with PC2
and regulating its function [Mai et al.,
2005; Wang et al., 2007; Kim et al.,
2008]. Importantly, mutant Pkhd1 mice
present with hepatic, pancreatic and
renal defects and cilia in these animals
are significantly shorter than in controls
[Woollard et al., 2007].
In renal tubules, PC1 and PC2 have
been proposed to mediate Ca2þ signaling upon ciliary bending, similarly to the
putative role of cilia and PC2 in LR
determination [Praetorius and Spring,
2001; Pennekamp et al., 2002; McGrath
et al., 2003; Nauli et al., 2003]. Additionally, PC1 positive exosome-like
vesicles (ELV), also enriched for various
signaling molecules, have been found in
urine and attached to renal epithelia cilia
leading to the speculation that a model
similar to the nodal vesicular parcel is
also operating in the kidney [Pisitkun
et al., 2004; Harris and Torres, 2009;
Hogan et al., 2009]. However, two
independent groups have shown that
the cystic kidney phenotype resulting
from disruption of Pkd1, Tg737, or
Kif3a depends on the developmental
time at which these genes are inactivated
[Davenport et al., 2007; Piontek et al.,
2007]. Using mice with a conditional
Pkd1 allele, Piontek et al. have shown
that the controlled inactivation of Pkd1
before postnatal day 13 results in cysts in
3 weeks whereas animals in which the
gene is disrupted at day 14 or later
develop cysts after 5 months [Piontek
et al., 2007]. These data led the authors
to suggest that the homeostasis of the
tissue might present different requirements of ciliary mediated flow sensing
during development or in the adult
kidney and also that other mechanisms
are likely involved in determining the
onset and progression of cystic kidney
disease [Davenport et al., 2007; Piontek
et al., 2007].
Ciliary Dysfunction: A Unifying
Defect in Cystic Kidney Disease
The link between cilia and cystogenesis
is not restricted to PKD but rather it has
been postulated to be the unifying
cellular defect underlying most if not
all CDKs [Watnick and Germino,
2003; Hildebrandt and Otto, 2005].
This concept is supported by studies
in nephronophthisis (NPHP; OMIM
256100), an autosomal recessive cystic
kidney disease and the most frequent
genetic cause of end stage renal disease in
children and young individuals. It is
characterized by the formation of corticomedulary cysts, interstitial fibrosis and
renal insufficiency. In addition, NPHP
can present associated with extra-renal
phenotypes such as retinal degeneration
in Senior–Løken syndrome (SLSN;
OMIM 266900) and cerebellar vermis
hypoplasia in Joubert syndrome (JS;
OMIM 213300). NPHP is a genetically
heterogeneous disorder for which nine
genes (NPHP1-9) have been cloned
to date [Hildebrandt et al., 2009 and
references within]. Initially, the characterization of the proteins encoded by
NPHP1 and NPHP2/INVS, nephrocystin-1 and inversin respectively, show
that these proteins localize to primary
cilia in renal tubular epithelial cells
where they form a complex with
b-tubulin [Otto et al., 2003]. Overall,
the characterization of the
proteins encoded by NPHP1
nephrocystin-1 and inversin,
respectively, show that these
proteins localize to primary
cilia in renal tubular epithelial
cells where they form a complex
with b-tubulin
the characterization of all the nephrocystins has revealed a cellular localization
pattern involving the primary cilium and
the basal body [Table II; reviewed by
Hildebrandt et al., 2009].
Ciliary Dysfunction Can Cause
a Broad Range of Phenotypes
In addition to cystic kidney disease, LR
patterning defects and retinal degeneration, ciliary dysfunction can result in a
broad spectrum of disorders that range
from PKD to highly pleiotropic syndromes: the ciliopathies [Table I; Badano
et al., 2006a; Sharma et al., 2008]. This
classification is based in the fact that a
common, or at least overlapping, cellular
defect is central in the etiology of
the different clinical entities. Therefore,
this concept per se assigns levels of
complexity not previously recognized
or expected for a once thought vestigial
organelle and poses the question of why
alterations in a particular cellular structure can give rise to the numerous,
sometimes apparently unrelated, phenotypes that define and characterize the
A first clue to answer this question
comes from the observation that virtually all cell types in the human body
are either ciliated or have the capacity
to become so (http://www.bowserlab.
Thus, ciliary dysfunction will likely
affect numerous tissues and organs, albeit
to different degrees, depending on the
specific ciliary defect, the pattern of
expression of the altered ciliary gene and
the functional dependency of the tissue
with respect to the cilium. Second,
several ciliary proteins likely play important extraciliary roles adding another
layer of complexity and complicating the
dissection of the specific role/s of cilia in
the pathogenesis of different ciliopathy
phenotypes. Finally, recent data have
several ciliary proteins likely
play important extraciliary
roles adding another layer of
complexity and complicating
the dissection of the specific
role/s of cilia in the
pathogenesis of different
ciliopathy phenotypes.
shown that cilia actively participate
in the transduction of key signaling
cascades that participate during development and tissue homeostasis thus broadening the spectrum of phenotypes that
can be caused by their dysfunction.
Understanding the Cellular Basis
of Cystogenesis and Other
Phenotypes: Wnt Signaling
Provided the initial link between a
cellular defect and a particular phenotype, the challenge becomes to understand the exact biological process that is
being perturbed. Regarding the role of
cilia in cystogenesis, important insight
came from studies showing that
NPHP2/inversin is critical to regulate
Wnt signaling [Simons et al., 2005]. The
Wnts are a family of secreted factors that
bind Frizzled receptors to activate distinct signaling cascades depending on
the specific Wnt activator, the receptor
and also the activity of Disheveled (Dvl),
a molecular switch between signaling
cascades. Canonical Wnt signaling acts
through b-catenin which drives the
expression of a number of TCF-LEF1
responsive genes to control proliferation, cell cycle progression, differentiation and development [Grigoryan et al.,
2008] while the non-canonical planar
cell polarity (PCP) signaling pathway
provides cells with positional clues that
are required for concerted multicellular
actions such as convergence and extension (CE) movements during gastrulation and neurulation and the correct
organization of tissues [Veeman et al.,
2003]. Upon activation of the pathway,
the subcellular localization of Dvl
appears to determine the final signaling
outcome whereby nuclear localization
of Dvl, which represses the b-catenin
destruction complex composed of
GSK3b, APC and axin, is required for
canonical Wnt signaling while membrane bound Dvl favors the PCP pathway [reviewed by Veeman et al., 2003;
Gerdes and Katsanis, 2008]. Importantly,
inversin has been shown to interact with
Dvl targeting it for degradation and thus
mutations in NPHP2 result in impaired
control of the Wnt pathway and defective PCP [Simons et al., 2005]. Therefore, ciliary signaling, likely acting
through proteins such as inversin, is
thought to be required to modulate the
balance between Wnt signaling pathways (Fig. 2A).
These data provided important
insight into the cellular basis of different
phenotypes associated with ciliary dysfunction. In the mouse model inversion
of embryonic turning (inv) where inversin is disrupted, nodal cilia present
defective orientation, which results in
abnormal movement and decreased
nodal flow explaining the characteristic
LR defects of these animals [Okada et al.,
1999, 2005]. Importantly, the position
and posterior tilt of the cilium in nodal
cells, likely requiring PCP signaling,
have been shown to be critical for proper
beating and flow generation [Nonaka
et al., 2005; Okada et al., 2005].
Regarding cystic kidney disease, the
Wnt pathway plays a critical role in
the formation and maintenance of the
kidney where it is required for the
induction of the metanephric mesenchyme to develop the proximal portions
of the nephron and for the regulation
of cell proliferation [Simons and Walz,
2006; Bacallao and McNeill, 2009].
Interestingly, both PCP defects and
hyperactivity of canonical Wnt signaling in transgenic mice overexpressing
b-catenin can result in the formation
of cysts [Saadi-Kheddouci et al., 2001;
Simons et al., 2005]. One mechanistic
model linking PCP and cystogenesis is
based on the observation that a great
percentage of dividing cells in the renal
tubules orient their mitotic spindles
parallel to the lumen and thus the net
result of cell division is tubular elongation and not dilation [Fig. 2B; Fischer
et al., 2006]. Importantly, misoriented
mitotic spindles have been observed in
both mouse and rat models of cystic
kidney disease [Fischer et al., 2006].
Although the nature of the signal(s)
that cilia are sensing to regulate Wnt
signaling is still not entirely clear,
studies on Bardet–Biedl syndrome
Although the nature of the
signal(s) that cilia are sensing to
regulate Wnt signaling is still
not entirely clear, studies on
Bardet–Biedl syndrome
support the role of cilia and
basal bodies as critical players
to maintain the correct balance
between different Wnt
signaling outcomes
(BBS; OMIM 209900) support the role
of cilia and basal bodies as critical players
to maintain the correct balance between
different Wnt signaling outcomes
Normal PCP
Fluid Flow
Mitotic spindles
parallel to the lumen
Disrupted PCP
Perturbed ciliary
Dvl degradation
Dvl relocalization
Aberrantly positioned
mitotic spindles
Non-canonical Wnt
Canonical Wnt
Figure 2. Cilia-mediated Wnt signaling and its role in cystogenesis. A: Representation of a cilium/basal body, denoting their role in
modulating the balance between canonical and non-canonical PCP signaling. In conditions of normal ciliary/basal body signaling,
molecules such as Inversin (Inv) are required to favor PCP over canonical signaling by inhibiting Dvl and activating the b-catenin destruction
complex composed of Axin, GSK3-b and APC. In contrast, perturbation of the basal body (i.e., mutations in the BBS proteins) or ciliamediated signal transduction results in decreased PCP and the concomitant upregulation of canonical signaling. B: Representation of the
model linking perturbed PCP signaling with cystogenesis where lack of positional clues due to perturbed PCP signaling results in aberrantly
positioned mitotic spindles leading to tubule dilation as opposed to extension [adapted from Germino 2005].
[Fig. 2A; review by Gerdes and Katsanis,
2008]. BBS is a disorder characterized by
obesity, mental retardation, polydactyly,
retinal degeneration and renal malformations including the formation of
cysts [Zaghloul and Katsanis, 2009]. To
date, 14 BBS genes (BBS1-12, MKS1,
NPHP6/CEP290) have been identified
[Stoetzel et al., 2007; Leitch et al., 2008
and references within]. The BBS proteins localize primarily to centrosomes
and basal bodies and several of them
can be found forming a complex, the
BBSome, that localizes to the pericentriolar region and the ciliary membrane
and has been implicated in ciliogenesis
[Ansley et al., 2003; Fan et al., 2004; Kim
et al., 2004, 2005; Li et al., 2004; Badano
et al., 2006a; Nachury et al., 2007;
Loktev et al., 2008]. Interestingly, depletion of different BBS proteins in mice
and zebrafish result in characteristic
PCP phenotypes [reviewed by Wang
and Nathans, 2007]. Bbs6/, bbs1/
and bbs4/ mice present with exencephaly, misoriented stereociliary bundles
in the cochlea and open eyelids, a
phenotype thought to be caused by
defective convergence of epithelial
cells, similar to the defect underlying
neural tube closure. In zebrafish, depletion of bbs proteins result in failure
to achieve the concerted migration
and intercalation of cells in the embryonic midline that characterize CE
movements during gastrulation and
thus, mutant embryos present with a
shorter body axis, defective somitic
definition and abnormally shaped notochords. In addition, a genetic interaction
between the bbs genes and core PCP
genes such as vangl2 was also demonstrated [Ross et al., 2005; Badano et al.,
More recently, it has been shown
that the BBS proteins modulate the
balance between canonical Wnt and
PCP signaling whereby loss of BBS
function leads to PCP defects and the
concomitant upregulation of canonical
Wnt through the stabilization of
b-catenin [Gerdes et al., 2007]. Interestingly, depletion of BBS proteins leads to
altered proteasome activity in Hek293
cells suggesting that protein clearance
defects could at least contribute to the
accumulation of b-catenin although this
possibility needs further evaluation
[Gerdes et al., 2007]. Importantly, this
increased functional complexity associated with the BBS proteins might be
a consequence of their potential ciliary
and extraciliary roles. For example,
depletion of BBS4 in mammalian cells
results in structural and functional
centrosomal defects [Kim et al., 2004].
Importantly, in addition to its role
during cell division, the centrosome
has been shown to be important in cell
migration and protein clearance and
thus, perturbation of the BBS proteins
might affect extra-ciliary processes
likely relevant to the pathogenesis of
this syndrome and other ciliopathies
[Badano et al., 2005]. Similarly, ALMS1,
the protein mutated in Alström syndrome (ALMS; OMIM 203800), also
localizes to basal bodies and centrosomes
[Hearn et al., 2005]. Furthermore,
complete knockdown of Alms1 in mice
results in ciliogenesis defects [Li et al.,
2007]. The ALMS phenotype is highly
reminiscent of BBS in that is characterized by obesity, retinal dystrophy,
cardiomyopathy, diabetes but present
with sensorineural deafness and no
Wnt misregulation is not exclusive
of BBS and NPHP given that it is
characteristic of other ciliary mutants.
In Kif3a/ mice, canonical Wnt signaling is increased [Corbit et al., 2008]
and in vitro reporter assays to quantify
b-catenin activity showed that depletion
of KIF3A and different BBS proteins
results in cells that are hyper-responsive
to Wnt stimuli [Gerdes et al., 2007].
Also, Ift88orpk/orpk and Ofd1/ mice
present similar Wnt defects [Corbit
et al., 2008]. Ofd1 is the mouse ortholog
of OFD1, the gene mutated in orofaciodigital syndrome type I (OFD1;
OMIM 311200), a ciliopathy characterized by malformations involving the oral
cavity, face and digits that often present
with central nervous system defects and
cystic kidney disease [Ferrante et al.,
Shh Signaling Defects in
the Ciliopathies
Hedgehog (Hh) signaling regulates morphogenesis, patterning and growth of
different tissues and organs and therefore
several ciliopathy phenotypes, including
polydactyly, neural tube and brain defects
Hedgehog (Hh) signaling
regulates morphogenesis,
patterning and growth of
different tissues and organs and
therefore several ciliopathy
phenotypes, including
polydactyly, neural tube
and brain defects can be
consequences of
alterations in this pathway.
(Table I), can be consequences of
alterations in this pathway. In mammals,
Sonic Hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dhh)
compose a family of Hh secreted signaling proteins that bind the Patched
receptor (Ptc) to activate different
signaling cascades. Upon binding of
Shh, patched 1 (Ptc1) is inactivated
and Smoothened (Smo) is released to
block the processing of Gli3 into its
repressor form (Gli3R) thus enabling
Gli-mediated target gene regulation
[Varjosalo and Taipale, 2008]. Although
the mechanism is not completely understood, the subcellular localization of the
different components of the pathway is
important for activity and the cilium and
IFT appear as key components of the
signaling apparatus (Fig. 3).
Initially, a mouse mutagenesis
screen uncovered two novel embryonic
patterning mutants, wimple (wim) and
flexo (fxo), that presented characteristic
Shh defects such as open neural tube,
brain and limb abnormalities. Interestingly, the wim and fxo phenotypes, also
characteristic of Kif3a mutants, were
shown to be caused by a mutation in
IFT172 and by a novel hypomorphic
allele of IFT88, respectively [Huangfu
et al., 2003]. Subsequently, it has been
shown that Smo translocates into the
cilium upon Shh stimulation and that
ciliary localization is essential for Smo
activity [Corbit et al., 2005; Aanstad
et al., 2009]. Furthermore, Ptc1 localizes
to the primary cilium and inhibits Smo
No Shh ligand
Upon Shh stimulation
Hedgehog responsive genes
Hedgehog responsive genes
Figure 3. The cilium and sonic hedgehog (Shh) signaling. In the absence of Shh
(left), the receptor patched (Ptc1) is localized to the cilium, preventing the ciliary
accumulation of smoothened (Smo) and thus favoring the processing of the Gli3
transcription factor into its transcriptional repressor form (Gli3R). Upon binding of Shh
(right), Ptc1 is translocated outside the ciliary compartment allowing Smo to enter it in a
process that depends on the anterograde IFT machinery. The ciliary accumulation of Smo
in turn inhibits the processing of Gli into Gli3R while favors the processing of Gli3 into
the activator form that is able to drive the expression of different target genes.
activity by preventing its accumulation
in the ciliary compartment. Upon Shh
binding, Ptc1 is translocated out of the
cilium and Smo is able to enter it in
a process that requires b-arrestins and
Kif3a [Fig. 3; Rohatgi et al., 2007;
Kovacs et al., 2008]. Additionally, Gli1,
Gli2, and Gli3 localize to cilia and loss of
IFT88 leads to altered Gli2 and Gli3
processing [Haycraft et al., 2005].
In general, ciliogenesis and normal
ciliary function appear to be critical to
maintain Hh signaling as demonstrated
by different IFT mutants that are characterized by severe developmental
abnormalities attributable to defective
Hh transduction [reviewed by Eggenschwiler and Anderson, 2007]. Briefly,
mutations in IFT139, mutated in the
alien mouse (aln), result in abnormal
primary cilia and overactivation of Shh
[Tran et al., 2008]. Mutations in the
retrograde IFT dynein motor Dnchc2
and the basal body protein Ftm1 also
result in abnormal Gli3 processing and
mutant animals present with neural tube,
LR and limb patterning defects [May
et al., 2005; Vierkotten et al., 2007].
Importantly, defective Shh signaling
can readily explain several of the phenotypes that characterize the ciliopathies
and significant progress is being made to
understand the role of this signaling
cascade in their pathogenesis. Using
conditional mutants to circumvent the
lethality in complete ciliary nulls, it has
been shown that ablation of Kif3a in the
developing limb leads to aberrant Hh
signaling (both Shh and Ihh) and results
in polydactyly and altered digit patterning [Haycraft et al., 2007]. Similarly,
depletion of Kif3a in cartilage results in
skeletogenesis defects such as alterations
in growth plate organization and excessive intramembranous ossification,
defects that correlate with altered Hh
signaling both on the level and field of
expression of different components of
the pathway [Koyama et al., 2007]. A
skeletal dysplasia characterized by short
ribs and limbs, polydactyly, and wrist
bones malformations is Ellis-van Creveld syndrome (EvC; OMIM 225500).
Interestingly, EVC, mutated in this
condition, encodes a protein that localizes to the base of chondrocyte cilia and
is required for Ihh signaling in the
growth plate [Ruiz-Perez et al., 2007].
Jeune asphyxiating thoracic dystrophy
(JATD; OMIM 208500) is a rare chondrodysplasia where patients present a
severely constricted thoracic cage and
respiratory insufficiency often lethal
in the first years of life. In addition,
polydactyly, kidney/liver/pancreas cysts
and retinal degeneration are also present
in these patients. Importantly, mutations
in IFT80 and DYNC2H1 (cytoplasmic
dynein 2 heavy chain 1) are found in
JATD [Beales et al., 2007; Dagoneau
et al., 2009].
Ablation of either Ift88 or Kif3a in
different neuronal populations have
demonstrated the need for intact Shh
signaling to maintain neural progenitor
pools both in the dentate gyrus and the
cerebellum [Chizhikov et al., 2007; Han
et al., 2008; Spassky et al., 2008]. In the
cerebellum, it has been shown that ciliamediated Shh signaling is required to
maintain and expand the pool of granule
cell precursors (GCPs). Consequently,
specific ablation of Ift88, Kif3a, or Smo in
cerebellar GCPs results in reduced
expansion of this group of cells and
cerebellar hypoplasia [Chizhikov et al.,
2007; Spassky et al., 2008]. Joubert
syndrome (JS) is a group of disorders
characterized by brain malformations
that include cerebellar vermis hypoplasia
and brainstem abnormalities, the molar
tooth sign (MTS) in radiological examination. Patients can also present cystic
renal disease, nephronophthisis, mental
retardation, polydactyly, retinal degeneration, breathing problems and hypotonia among other clinical manifestations [reviewed by Parisi et al.,
2007]. To date, mutations in seven genes
have been causally linked to JS and
ciliary dysfunction appears central in the
etiology of JS as highlighted by the fact
that several of the mutated proteins not
only localize to basal bodies, centrosomes and cilia but also have been
implicated in other ciliopathies as is the
case for NPHP1, NPHP6/CEP290,
MKS3/TMEM67, and NPHP8/
RPGRIP1L [Table II; Parisi et al.,
2007; Sharma et al., 2008 and references
within]. Therefore, the cerebellar
abnormalities that characterize JS, a
common finding among other ciliopathies (Table I), might result from altered
Shh signaling and the inability to maintain and expand the population of GCPs.
Other Signaling Cascades: PDGF
Signaling and FGF-Mediated
Control of Ciliogenesis
Another signaling pathway that has
been recently shown to operate through
the cilium is platelet derived growth
factor receptor alpha (PDGFRa). Stimulation of PDGFRaa (PDGFRa
homodimer) by PDGFaa results in
autophosphorylation events that lead to
the activation of downstream signaling
cascades mediated by AKT and Mek1/
2-Erk1/2, that ultimately regulate cell
cycle progression, survival and cell
migration [reviewed by Christensen
et al., 2008]. Interestingly, it has been
shown that PDGFRa is upregulated
during ciliogenesis and localizes to the
primary cilium in NIH3T3 and mouse
embryonic fibroblast arrested cells. Furthermore, the ciliary localization of
PDGFRa is required for proper activation and embryonic fibroblasts derived
from Ift88orpk mice failed both to
upregulate the receptor and activate the
pathway [Schneider et al., 2005].
While different signaling pathways
require the cilium to operate, recent data
indicates that other cascades might exert
their actions, at least in part, through the
direct regulation of ciliogenesis. Neugebauer and colleagues demonstrated
that fibroblast growth factor (FGF)
signaling regulates ciliogenesis, cilia
length and function in epithelial cells
in zebrafish and Xenopus [Neugebauer
et al., 2009]. Importantly, FGF regulates
developmental processes such as LR
determination and convergent extension movements during gastrulation
[Meyers and Martin, 1999]. Inhibition
of FGF signaling through either morpholino-mediated depletion of FGF
receptor 1 (Fgfr1), dominant negative
mutants or pharmacological agents led
to a reduction in the length of cilia and
perturbed fluid flow in Kupffer’s vesicle
and other ciliated cell types in zebrafish.
Similarly, in Xenopus embryos, defective FGF signaling results in shorter cilia
in the LR organizer, the gastrocoel
roof plate. Interestingly, FGF signaling
has been shown to regulate the prociliogenic transcription factors foxj1 and
rfx2 and ift88 [Neugebauer et al., 2009].
Furthermore, Hong and Dawid [2009]
were able to show that Ier2 and Fibp1,
two downstream targets of FGF signaling, regulate ciliogenesis in Kupffer’s
vesicle and mutations in these genes
result in LR defects in zebrafish. Thus,
defective FGF can result or contribute to
several of the phenotypes observed in
ciliary mutants, highlighting the complexity underlying each of the biological
processes regulated by the cilium where
distinct signaling pathways need to
interact to control biological processes
in a coordinated fashion.
Given the ubiquitous distribution
of cilia, their involvement in multiple
signaling cascades and the plethora of
biological processes that these cascades
regulate, it is not surprising that complete absence of cilia is generally incompatible with life. Therefore, defective
ciliogenesis should result in the more
severe phenotypes. One syndrome that
lies at the severe end of the ciliopathy
phenotypic spectrum is Meckel–Gruber
syndrome (MKS; OMIM 249000;
Table I). MKS is a lethal condition
characterized by occipital encephalocoele, neural tube defects, cystic kidney
disease, hepatic fibrosis, polydactyly and
cleft palate [Alexiev et al., 2006]. Six
MKS loci have been mapped to date
from which five genes have been
identified: MKS1, MKS3, CEP290,
[Kyttälä et al., 2006; Smith et al., 2006;
Delous et al., 2007; Baala et al., 2007a;
Tallila et al., 2008]. Importantly, the
characterization of these genes/proteins
has demonstrated that MKS is a ciliopathy that likely results from ciliogenesis
defects. MKS1 and MKS3 localize to the
basal body of cilia and are required for
its migration to underneath the apical
membrane during ciliogenesis [Dawe
et al., 2007]. Interestingly, MKS1 con-
tains a protein motif (B9 domain) that
albeit of unknown function, is shared by
two other proteins, MKS1-related proteins 1 and 2 (MKSR-1 and MKSR-2)
and is found exclusively in ciliated
organisms. Knockdown experiments in
cells have shown that similarly to MKS1,
MKSR-1 and MKSR-2 are also implicated in ciliogenesis in mammalian cells
[Bialas et al., 2009]. More recently, it was
shown that fibroblast cells from MKS
patients bearing mutations in MKS6/
CC2D2A lack cilia [Tallila et al., 2008].
Interestingly, the other two MKS genes,
CEP290 and RPGRIP1L/MKS5, are
also linked to cilia. CEP290 is a basal
body protein also implicated in the
pathogenesis of NPHP, JS and BBS
[Sayer et al., 2006; Valente et al., 2006;
Baala et al., 2007a; Leitch et al., 2008]
and RPGRIP1L/MKS5 encodes a basal
body protein mutated in JS [Delous
et al., 2007] (Table II). Thus, the analysis
of the different MKS proteins strongly
supports a ciliary defect as the underlying
cause of this disorder and also highlights
the complex genetics of the ciliopathies
whereby mutations in the same gene
can result in seemingly distinct clinical
The concept of a ciliopathy implies that
different clinical entities share a common cellular defect and an overlapping
set of phenotypes (Table I). Importantly,
The concept of a ciliopathy
implies that different clinical
entities share a common cellular
defect and an overlapping
set of phenotypes. Importantly,
the identification of typical
phenotypic outcomes of ciliary
dysfunction has provided
a predictive tool when
attempting to gain insight into
the cellular basis of disorders
of unknown etiology.
the identification of typical phenotypic
outcomes of ciliary dysfunction has
provided a predictive tool when
attempting to gain insight into the
cellular basis of disorders of unknown
etiology. An example is JATD that was
predicted to be a ciliopathy before causal
genes were identified, based solely on
clinical features that overlap with those
of other known ciliopathies such as
cystic kidneys, brain malformations,
polydactyly, and skeletal defects [Badano
et al., 2006b]. Additionally, our
improved knowledge has also resulted
in a positive feedback loop affecting the
genetic dissection of the ciliopathies by
allowing for example the possibility of
filtering a list of candidate genes in a
genomic locus according to whether the
genes encode ‘‘ciliary proteins’’ or not.
In this context, a multi-group effort has
led to the identification of a number of
genes/proteins involved in ciliary biology which have been integrated in a
non-redundant list: the ciliary proteome
[Gherman et al., 2006 and references
For example, the categorization of BBS
as a ciliopathy and the availability of the
ciliary proteome has greatly facilitated
the identification of several BBS genes
such as for example BBS3, BBS5, and
BBS12, by prioritizing candidate genes
and first sequencing those included in
the ciliary proteome [Fan et al., 2004; Li
et al., 2004; Stoetzel et al., 2007].
Another important implication of
the ciliopathy concept is that alterations
in different genes can result in overlapping phenotypic features and thus
a first possibility is that mutations in
different genes can cause the same
disorder. It is interesting to note that
the majority of the ciliopathies are
genetically heterogeneous disorders
(Table II). In addition, it has been shown
that disorders historically considered as
mendelian traits can present more complex patterns of disease transmission,
oligogenic inheritance, whereby mutations in more than one locus segregate
Another important implication
of the ciliopathy concept is that
alterations in different genes
can result in overlapping
phenotypic features and thus a
first possibility is that
mutations in different genes can
cause the same disorder. It is
interesting to note that the
majority of the ciliopathies
are genetically heterogeneous
with the disease in families. For example
in some BBS families, three mutant
alleles involving bona fide BBS genes as
well as second site modifiers, collaborate
to modulate the penetrance and expressivity of the disorder [for some references
see Katsanis et al., 2001; Beales et al.,
2003; Badano et al., 2006a]. Similarly,
mutations in more than one NPHP gene
have also been detected in patients
showing that in some families at least,
NPHP can be inherited as an oligogenic
trait [Hoefele et al., 2007]. Furthermore,
it has been shown that epistatic interactions between mutant alleles in different genes can greatly influence the
expressivity of the disease in NPHP
patients. While alterations in NPHP1 are
mainly associated with nephronophthisis, the presence of additional mutations
in NPHP6 and AHI1 can determine the
development of neurological symptoms
associated with JS [Tory et al., 2007].
The later example introduces
a second possibility in that mutations
in a given gene might be related to
distinct clinical entities either as causal
or modifying factors (see Syndrome
column in Table II). For example,
RPGRIP1L contribute alleles to the
pathogenesis of NPHP, JS, and MKS
and it was recently shown that a specific
allele of this gene is a modifier of the
retinal phenotype of ciliopathy patients
bearing mutations at other loci [Arts
et al., 2007; Delous et al., 2007; Wolf
et al., 2007; Khanna et al., 2009].
Mutations in CEP290 have been found
associated with NPHP (NPHP6), JS,
MKS and BBS [Sayer et al., 2006;
Valente et al., 2006; Baala et al., 2007a;
Frank et al., 2008; Leitch et al., 2008].
Likewise, MKS3 mutations have been
identified in JS patients [Baala et al.,
2007b; Brancati et al., 2009]. Another
example is provided by BBS and MKS,
two disorders significantly similar at the
phenotypic level (Table I). Interestingly,
mutations in BBS2, BBS4, and BBS6
have been found in MKS-like fetuses
[Karmous-Benailly et al., 2005] and
more recently, it was shown that mutations in MKS1, MKS3, and CEP290 are
found in BBS patients as either causal or
modifier alleles [Leitch et al., 2008].
These data raise the question of why
mutations in the same gene can result in
different clinical manifestations. In some
cases, the specific mutated gene determines the final outcome as is the case in
Senior–Løken syndrome where although
different NPHP genes can cause it,
mutations in NPHP5 are invariably
associated with it. Importantly, nephrocystin-5 localizes to the photoreceptors
and interacts with calmodulin and the
retinitis pigmentosa GTPase regulator
(RPGR), a gene mutated in retinitis
pigmentosa [Otto et al., 2005]. In other
cases, the different phenotypic outcome
does not present a clear correlation with
localization or pattern of expression but
rather seems to depend on the type of
mutation and its impact on protein
function. In BBS for example, in vivo
assessment of the pathogenic effect of the
mutations found in the MKS genes has
shown that while mutations normally
associated with the lethal MKS phenotype are complete nulls, residual activity
is observed in the MKS proteins with
BBS-associated mutations [Leitch et al.,
2008]. Recently, likely hypomorphic
mutations in MKS3 have been identified
in patients with NPHP and liver fibrosis
[Otto et al., 2009]. Similarly, it was
shown that while a hypomorphic mutation in Nphp3 in the pcy mouse model
results in cystic kidney disease, complete
loss of Nphp3 results in a pleiotropic
lethal phenotype that includes congenital heart defects and situs inversus, and
in humans a MKS-like phenotype
[Bergmann et al., 2008]. Altogether,
these data indicate that the ciliopathies,
albeit they can be recognized as distinct
clinical entities, represent a continuum
of disease severity where the position of
any given disorder is determined by the
specific gene that is mutated, its biological role and pattern of expression,
the total mutational load across different
ciliary genes, and importantly, the type
and effect of the mutations on protein
In the last decade, a plethora of biological roles have been assigned to cilia
including photoreception, mechanosensing, and paracrine signaling transduction. This in turn has translated into
important progress in our understanding
of the cellular basis of different phenotypes that characterize the ciliopathies
such as for example cystic kidney disease.
Other phenotypes however have proven
to be more difficult to understand and
dissect. One particular example is obesity, a hallmark of several ciliopathies,
particularly BBS and ALMS (Table I).
Bbs mutant animals show hyperphagia
and present elevated leptin levels [for
some references see Fath et al., 2005;
Eichers et al., 2006; Zaghloul and
Katsanis, 2009]. Furthermore, in Bbs2/
and Bbs4/ neurons, the ciliary localization of somatostatin receptor type 3
(Sstr3) and melanin-concentrating hormone receptor 1 (Mchr1), which is
involved in the regulation of feeding
behavior, is lost [Berbari et al., 2008].
Other clues have been provided by
conditional mutants of Ift88 showing
that disruption of the gene in proopiomelanocortin (POMC) neurons in
the hypothalamus results in mice that are
obese, hyperphagic, and have elevated
leptin levels [Davenport et al., 2007].
Interestingly, the BBS proteins appear to
be required for leptin receptor (LepR)
intracellular trafficking in hypothalamic
neurons and thus it has been suggested
that the LepR signaling defect observed
in Bbs2/, Bbs4/, and Bbs6/ mice
might be due to impaired targeting of the
receptor to the plasma membrane or the
cilium, similarly to the ciliary localization requirements of components of the
Shh signaling cascade [Seo et al., 2009].
Besides this putative role of the cilium in
neurons, a recent report indicates that
cilia and the BBS proteins are required
for proper adipocyte differentiation
whereby depletion of BBS proteins
favors adipogenesis suggesting that the
obesity phenotype might result from
defects at multiple levels [Marion et al.,
A deeper understanding of the role
of cilia in different tissues and the phenotypes that result from their absence or
malfunction not only has provided a
means to predict novel ciliopathies but
has also facilitated the identification of
novel phenotypes in ciliopathy patients.
Given that olfactory neurons present
highly specialized cilia that are important
for odorant perception it was hypothesized that a cilia-related phenotype
would be anosmia, a prediction that was
subsequently proven in BBS patients
[Kulaga et al., 2004]. Similarly, it was
shown that Bbs1 and Bbs4 mutant mice
present thermosensory defects due to
problems with peripheral ciliated sensory
neurons, a phenotype that also is present
in BBS patients and was not previously
recognized in the clinic [Tan et al., 2007].
Therefore, our knowledge regarding the
cellular basis of these human conditions
has led to a better clinical characterization of patients providing important
data for diagnostic, counseling and
eventually treatment purposes.
The success linking ciliary function with
diverse biological processes has been
impressive. The challenge has become
to start elucidating the exact role that the
cilium is playing in each case and equally
important, why tissues and organs are
affected differently by defects in ciliary
function. Undoubtedly one important
variable to consider is the pattern of
expression of the ciliary gene/s. At
the same time however, the fact that a
number of ciliary genes are expressed
differentially between ciliated tissues
reflects the multiple and diverse roles
that these organelles are playing in
different contexts highlighting the need
to characterize ciliary proteins in physiologically relevant settings. To this end,
animal models in which the gene of
interest is perturbed in a tissue specific
and/or temporally regulated manner are
proving to be extremely powerful and
some examples have been mentioned in
this review. Another likely underestimated issue that complicates the study of
ciliary proteins is that many of them
appear to have extraciliary roles. In
addition to some of the examples
provided in this review, PC2, the Ca2þ
channel required for mechanosensation
both in renal epithelial cells and in the
embryonic node, also localizes to the
plasma membrane and the endoplasmic
reticulum where it operates as an intracellular Ca2þ release channel [reviewed
by Tsiokas et al., 2007]. Similarly, several
NPHP proteins, including NPHP2/
inversin and NPHP1, localize to basal
bodies and cell–cell junctions [Nürnberger et al., 2002; Hildebrandt et al.,
One question that will likely be
answered as we dissect these issues is why
the different signaling cascades mentioned above need the cilium in the first
place. A priori, one plausible answer
seems to rely on the compartmentalization that the cilium permits, allowing
both the concentration and separation
of different moieties, and the use of
an efficient microtubule based transport
mechanism to rapidly relay information
from the cilium towards the centrosome,
the microtubule organizing center, and
into the nucleus. Considering this continuum then, it is not surprising that
in general, the phenotype in ciliopathy
patients or animal models appears to
depend on how globally is ciliary
function affected. Mutations in a protein
that needs to be localized to the cilium
(such as PC2) might result in a fairly
restricted phenotype while global ciliary
dysfunction (disrupted ciliogenesis in
MKS or basal body dysfunction in
BBS) probably affect, albeit to different
degrees, all the biological processes that
operate through the organelle resulting
in highly pleiotropic or lethal pheno-
types. In addition, one lesson from the
genetic dissection of ciliopathies is that
the degree of ciliary dysfunction, and
therefore the clinical manifestation, is
also influenced by the number and type
of mutations in different components of
the system. Importantly, the availability
of high-throughput mutational screening technologies, the development of
reliable functional assays to test coding
variants and our deeper understanding of
the cellular and genetic basis of these
disorders will likely have a beneficial
impact on the clinical management of
affected patients.
First of all we apologize to all those
scientists whose contribution to understand ciliary biology could not be
properly cited in this manuscript due to
space limitations. We also thank Cecilia
Gascue for her critical comments on
the manuscript. JLB and MCR are
supported by the Genzyme Renal Innovations Program (GRIP) and by Agencia
Nacional de Investigación e Innovación
(ANII), Programa de Apoyo Sectorial a
la Estrategia Nacional de Innovación INNOVA URUGUAY, DCI-ALA/
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