NDT Advance Access originally published online on February 14, 2008
Nephrology Dialysis Transplantation 2008 23(5):1500-1503; doi:10.1093/ndt/gfn033
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Mutations in RPGRIP1L: extending the clinical spectrum of ciliopathies*
Olivier Devuyst1 and
Véronique J. Arnould2
1 Division of Nephrology, Université catholique de Louvain Medical School, B-1200 Brussels
2 Division of Ophthalmology, Cliniques de l’Europe Saint-Michel, B-1040 Brussels, Belgium
Correspondence and offprint requests to: Oliver Devuyst, Division of Nephrology, Université catholique de Louvain Medical School, B-1200 Brussels, Belgium. E-mail: devuyst{at}nefr.ucl.ac.be
Keywords: cerebello-oculo-renal syndrome; Joubert syndrome; Leber congenital amaurosis; Meckel syndrome; Senior–Loken syndrome
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Introduction
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Identification of genes causing inherited cystic kidney diseases
has triggered a major interest for the concept of ‘ciliopathies’.
Indeed, almost all of the proteins involved in human renal cystic
diseases are expressed in the primary cilium complex located
in renal epithelial cells. Primary cilia are cellular extensions
containing a microtubule-based axoneme covered by a specialized
plasma membrane [
1]. The basal body of the cilia, which templates
the assembly of the microtubules, contains a centriole, which
itself is part of the centrosome. Primary cilia project into
the lumen, where they probably sense a variety of stimuli involved
in the regulation of cell proliferation and differentiation
[
2]. Primary cilia are present on almost all human cells, explaining
why ciliopathies affect multiple organs. However, the molecular
mechanisms, potential connections and clinical variability of
these diseases remain poorly understood. The study by Delous
et al. gives new insights into the field, by demonstrating that
mutations in the
RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting
protein 1-like) gene cause both Joubert syndrome (JBTS) and
Meckel syndrome (MKS), two complex diseases with neurological,
renal and ocular manifestations [
3]. The protein encoded by
RPGRIP1L is located in the primary cilium, and mutations impair
its interaction with nephrocystin-4, a protein involved in nephronophthisis.
Furthermore,
RPGRIP1L knockout mice show a phenotype similar
to that observed in foetuses with MKS. These findings, which
were also demonstrated in a companion article by Arts
et al.
[
4], highlight the importance of ciliary dysfunction in cerebello-oculo-renal
syndromes and nephronophthisis.
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Clinical and genetic heterogeneity of the Joubert and Meckel syndromes
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Joubert syndrome (JBTS) refers to a group of autosomal recessive
disorders characterized by a brainstem malformation creating
the ‘molar tooth sign’ (MTS) on axial magnetic resonance
imaging and neurologic manifestations that include cerebellar
ataxia, developmental delay, hypotonia, abnormal eye movements,
dysregulation of the breathing pattern and cognitive deficits.
Some JBTS patients also have retinal dystrophy and renal abnormalities.
In that case, JBTS is included among the cerebello-oculo-renal
syndromes (CORS) which, in addition to MTS, include renal (nephronophthisis
or cystic renal dysplasia) and retinal abnormalities (chorioretinal
colobomas, retinal dystrophy), and occasional hepatic fibrosis
and polydactyly [
5,6]. Up until now, four genes and two additional
loci have been associated with JBTS [
7–10] (
Table 1).
Mutations in two of these genes (
NPHP1 and
NPHP6) have been
associated with nephronophthisis, the most common genetic cause
of renal failure in children [
8,9]. Meckel (or Meckel–Gruber)
syndrome (MKS) is a rare and lethal autosomal recessive disorder
characterized by cystic kidney dysplasia and variably associated
central nervous system malformations (typically, posterior occipital
meningoencephalocele), hepatic ductal changes and cysts, and
polydactyly. MKS is caused by mutations in three genes (
MKS1,
TMEM67/MKS3 and
CEP290/
NPHP6), and a fourth locus has been described
[
10–12] (
Table 1). The identification of mutations in
TMEM67/MKS3 in JBTS patients [
10] and, inversely, mutations
in
CEP290/NPHP6 in MKS foetuses [
13] suggest that JBTS and MKS
may represent parts of a spectrum of cerebello-oculo-renal syndromes
involving ciliary proteins (
Table 1).
View this table:
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Table 1 Loci, causative genes and proteins involved in the overlapping Joubert syndrome (JBTS), cerebello-oculo-renal syndrome (CORS), Meckel syndrome (MKS), nephronophthisis (NPHP), Leber congenital amaurosis (LCA) and Senior–Loken syndrome (SLSN)
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RPGRIP1L mutations cause JBTS and MKS
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Using genome-wide linkage scans in consanguineous families in
which the known JBTS and MKS loci were excluded, Delous
et al.
identified a critical region on chromosome 16q [
3]. By examining
the syntenic region deleted in the
Ft (for fused toes) mouse,
which shows phenotypic resemblance to MKS, they identified a
candidate gene (
KIAA1005 or
RPGRIP1L) that was known to interact
with nephrocystin-4, a ciliary protein defective in nephronophthisis
[
14]. Sequencing of
RPGRIP1L uncovered nine mutations in five
families with CORS and two with MKS [
3]. Of note, 5/6 of the
individuals with CORS had at least one missense mutation, whereas
all foetuses with MKS harboured nonsense mutations. The individuals
with CORS and
RPGRIP1L mutations showed the neurological features
of JBTS, with nephronophthisis in 5/6 of the patients and slightly
enlarged cystic kidneys in one patient. All individuals with
CORS had ocular symptoms (oculomotor apraxia, ptosis, nystagmus),
but only one had retinitis pigmentosa, which is present in the
majority of individuals with
NPHP6 mutations [
9,
15,
16]. The
three foetuses with MKS originated from pregnancies terminated
at 15–16 weeks of gestation for severe cystic kidney dysplasia,
brain malformation and polydactyly, with further examination
disclosing bile duct proliferation, encephalocele and microphthalmia
[
3]. This severe phenotype resembled that of the
Rpgrip1l knockout
mice, which die in utero with exencephaly, microphthalmia, polydactyly,
and show renal proximal tubules cysts and ductal plate malformation
[
3].
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Functional characterization of RPGRIP1L
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Expression and functional studies yielded information about
the potential role of
RPGRIP1L [
3,4]. Like other genes involved
in JBTS-CORS and MKS,
RPGRIP1L is expressed early in the developing
eye, brain and kidney.
RPGRIP1L encodes the RPGRIP1L protein
which shares a significant homology with RPGRIP1, a ciliary
protein located in the photoreceptors in the retina where it
associates with CEP290/nephrocystin-6 [
17]. Mutations in either
RPGRIP1 or
CEP290/NPHP6 lead to Leber congenital amaurosis (LCA),
the most common cause of congenital blindness in infants and
children [
18,19]. It is known that RPGRIP1L binds directly to
nephrocystin-4 (nephroretinin), the product of
NPHP4 [
14]. Mutations
of
NPHP4 cause late-onset retinitis pigmentosa in addition to
nephronophthisis, an association described as Senior–Loken
syndrome [
20,21]. Of note, mutations of
RPGRIP1L detected in
individuals with CORS significantly decreased the binding between
RPGRIP1L and nephrocystin-4, potentially contributing to the
pathogenesis of the disease [
3,4]. Immunolocalization demonstrated
that RPGRIP1L co-localizes with nephrocystin-4 and nephrocystin-6
at the basal body–centrosome complex, and is also detected
along the axoneme and in the cytoplasm [
3,4] (
Figure 1).
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Fig. 1 Distribution of RPGRIP1L in the primary cilium. Schematic representation of the nonmotile primary cilium in a renal tubular epithelial cell. The central microtubular axoneme of the primary cilium, which is covered by a ciliary membrane, contains nine peripheral microtubule doublets that arise from the basal body via a transition zone at the base of the cilium. The basal body derives from the centrosome, itself constituted by a pair of perpendicular centrioles (each containing nine microtubule triplets). The assembly and maintenance of the cilium is mediated by a system of intra-flagellar transport (IFT) along the microtubule doublets in the axoneme, which is not represented here. Immunofluorescence microscopy of ciliated renal MDCK cells showed that endogenous RPGRIP1L co-localized at the basal body–centrosome complex with nephrocystin-4, nephrocystin-6 and the centrosome marker  -tubulin. In some cells, RPGRIP1L was also detected along the ciliary axoneme [3]. The co-localization of endogenous RPGRIP1L with nephrocystin-4 and nephrocystin-6 to the basal body was confirmed in renal tubular cells [4].
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The identification of disease-causing
RPGRIP1L mutations, their
functional analysis and the distribution of RPGRIP1L in the
basal body were also reported by Arts
et al. [
4]. Taken together,
these data show that RPGRIP1L interacts with ciliary proteins
and that mutations disrupting this interaction cause similar
phenotypes, supporting the role of ciliary dysfunction in these
diseases [
3,4]. The signalling events disrupted by defective
RPGRIP1L remain essentially unknown. In mice, RPGRIP1L is necessary
for the establishment of left–right asymmetry and patterning
of the neural tube and limbs, and is potentially involved in
the Hedgehog pathway [
22]. Since mutations of
RPGRIP1L account
for a small fraction of JBTS [
4], cloning of other causative
genes will probably elucidate these signalling mechanisms.
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Towards genotype–phenotype correlations?
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The pattern of mutations reported by Delous
et al. may suggest
a genotype–phenotype correlation in these diseases, with
residual function of the mutated proteins in pati- ents with
CORS contrasting with loss-of-function in foetuses with MKS
[
3]. However, Arts
et al. identified homozygous loss-of-function
mutations (both predicted to cause truncation before the interacting
domains of RPGRIP1L) in two consanguineous families with JBTS
and one missense mutation together with a nonsense mutation
in a family with overlapping JBTS–MKS syndrome [
4]. Clinical
heterogeneity could also reflect epistatic effects caused by
heterozygous mutations and/or variants in other causative genes
of JBTS/NPHP, as first reported by Tory
et al. [
15]. The low
prevalence of the retinal disease in CORS individuals harbouring
RPGRIP1L mutations could be due to partial redundancy of RPGRIP1
and RPGRIP1L proteins in different cell types [
3,4]. Alternatively,
this complication may not have developed in some of the younger
probands, as the age of onset of retinal dystrophy may be variable
[
21,
23].
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Conclusion and take-home message
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The studies of Delous
et al. [
3] and Arts
et al. [
4] extend
the clinical spectrum of ciliopathies, clarify their nosology
and highlight the importance of ciliary dysfunction in developmental
disorders that include renal manifestations. These results also
demonstrate the power of genome-wide linkage scans in carefully
selected families, and the usefulness of comparative genomics
in mouse models made available through random mutagenesis.
JBTS and MKS represent parts of a continuum of cerebello-oculo-renal syndromes probably linked to primary cilium dysfunction. These studies are relevant for the pathophysiology of nephronophthisis, Senior–Loken syndrome and Leber congenital amaurosis. Mutations of RPGRIP1L account for a small fraction of these diseases, and cloning of additional genes will help to understand signalling mechanisms and develop therapeutic approaches.
Conflict of interest statement. None declared.
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Notes
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* This article is based on the basic science article by Delous
M, Baala L, Salomon R
et al. The ciliary gene
RPGRIP1L is mutated
in cerebello-oculo-renal syndrome (Joubert syndrome type B)
and Meckel syndrome.
Nat Genet 2007; 39: 875–881.
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Received for publication: 30. 8.07
Accepted in revised form: 17. 1.08
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Introduction
Clinical and genetic...