In association with
Nephronophthisis (NPHP) is an autosomal recessive kidney disorder characterized by chronic
tubulointerstitial nephritis and leading to end-stage renal failure. NPHP as a renal entity is often part
of a multisystem disorder and has been associated with many syndromes including Joubert syndrome
(and related disorders) and Senior–Loken syndrome. Recent molecular genetic advances have allowed
identification of several genes underlying NPHP. Most of these genes express their protein products,
named nephrocystins, in primary cilial/basal body structures. Some nephrocystins are part of adherens
junction and focal adhesion kinase protein complexes. This shared localization suggests that common
pathogenic mechanisms within the kidney underlie this disease. Functional studies implicate nephrocystins
in planar cell polarity pathways, which may be crucial for renal development and maintenance of tubular
Nephronophthisis (NPHP) is an autosomal recessively
inherited renal disorder, which leads to progressive renal
failure, usually within the first 3 decades of life.1Nephro-
nophthisis literally means ‘disappearance of nephrons’.
Typical ultrasound features include normal or reduced
renal size, loss of corticomedullary differentiation and
corticomedullary cysts (Figure 1). Renal biopsy findings
include tubular atrophy, interstitial fibrosis and tubular
basement membrane defects, including abrupt transition
between thickening and attenuation or disintegration.2,3
A rare form of NPHP may lead to end-stage renal failure
(ESRF) within 5 years of age and is termed infantile NPHP.4
This differs from typical NPHP in that there is moderate
renal enlargement, histological changes that include
cortical microcysts, cystic dilatation of Bowman’s spaces
and lack of tubular basement membrane disruption.
NPHP is often part of a spectrum of multisystem disease
and may not be detected unless appropriate investigations
on relevant systems are performed. These disease associa-
tions form a very heterogeneous group (Table 1). The most
Received 23 July 2008; revised 4 November 2008; accepted 13 November
2008; published online 10 December 2008
Roslyn J Simms1,2, Lorraine Eley1and John A Sayer*,1,2
1Institute of Human Genetics, International Centre for Life, Newcastle
University, Central Parkway, Newcastle upon Tyne, UK;2Renal Services,
The Freeman Hospital, Newcastle Hospitals NHS Foundation Trust,
Newcastle upon Tyne, UK
*Correspondence: Dr JA Sayer, Institute of Human Genetics, International
Centre for Life, Newcastle University, Central Parkway, Newcastle upon
Tyne NE1 3BZ, UK. Tel þ44 191 2418608; Fax þ44 191 2418666;
European Journal of Human Genetics (2009) 17, 406–416; doi:10.1038/
ejhg.2008.238; published online 10 December 2008
Keywords: primary cilia; collecting duct; planar-cell polarity; urine
concentrating defect; tubulointerstitial nephritis
European Journal of Human Genetics (2009) 17, 406–416
& 2009 Macmillan Publishers LimitedAll rights reserved 1018-4813/09 $32.00
? Nephronophthisis (NPHP) is an autosomal recessive
kidney disease leading to end-stage renal failure in
children and young adults.
? Key histological findings in the kidney are tubulointer-
stitial fibrosis, tubular dilatation and cyst formation and
? NPHP is often a feature of a multisystem disease that may
include retinal dystrophy (Senior–Loken Syndrome) and
cerebello-ocular-renal syndromes (Joubert syndrome
and related diseases (JSRD)).
? NPHP may present with an early decrease in urinary
? End-stage renal failure (ESRF) typically occurs during
early teenage years, with the exception of the rare
infantile forms, where there is ESRF before 5 years of
? Molecular genetics now may allow easy detection of
the most common mutations (involving NPHP1 and
accounting for 25% of all cases).
? NPHP is a ‘ciliopathy’ as evidence to date implicates the
primary renal cilium and basal body apparatus in the
pathogenesis of NPHP.
? Patients need regular monitoring of renal and liver
function, eye examinations and preparation for renal
transplantation, which is the treatment of choice for
the renal failure that invariably ensues.
commonly associated syndrome is retinal dystrophy and
retinal degeneration leading to blindness (Senior–Loken
syndrome).1Other associations include Joubert syndrome
and related diseases (JSRD, reviewed in reference5), which
often involves a cerebellar, retinal and renal phenotype
referred to as CORS (cerebello-oculo-renal syndrome).
Apart from these, a whole variety of syndromes have been
reported in association with NPHP (Table 1).
NPHP has been reported worldwide, yet the incidence
varies. A Canadian study reported an incidence of 1 in
50000 live births,6whereas the incidence in the United
States of America was estimated to be 9 per 8.3 million.7A
more recent European study reported an incidence of
NPHP as 1 in 61800 live births.8However, as NPHP may
present in adults with late enuresis and renal failure,9these
figures may be an underestimate.
Core diagnostic criteria
NPHP is genetically and clinically heterogeneous. Tradi-
tionally, NPHP has been subdivided into infantile, juvenile
and adolescent forms, based on the age of onset of renal
failure. It remains useful to distinguish the much rarer
infantile NPHP from the more typical (non-infantile) forms
of NPHP, to allow a targeted approach to diagnosis and
molecular testing (Figure 2).
1. Early onset ESRF (less than 5 years of age)
2. Possible antenatal presentation with fetal oliguria and
3. Renal USS – normal sized or enlarged kidneys
4. Renal biopsy – interstitial fibrosis, tubular atrophy,
absence of tubular basement membrane irregularity,
renal cortical microcysts
5. Associated extrarenal features peculiar to infantile NPHP
include hypertension, situs inversus, ventricular septal
1. Median onset of ESRF 12 years (may be beyond 25 years)9
2. Polyuria and polydipsia (and salt wasting) in early
childhood (4–6 years of age)
3. Urinary concentration defect (o400mosm/kg in early
morning urine) that is not responsive to desmopressin
4. Growth retardation (secondary to salt wasting, dehydra-
tion and renal insufficiency)
5. Absence of (or minimal) haematuria and proteinuria
6. Renal USS – renal cortical hyperechogenicity, loss of
7. Renal biopsy – microscopy typically shows interstitial
nephritis, tubular atrophy and tubular dilatations.
Typically there is both thickening and attenuation of
the tubular basement membranes.
8. The clinical diagnosis of NPHP may be made (or looked
for) following detection of an associated extrarenal
disorder (see below and Table 2).
ultrasound scan demonstrating corticomedullary cysts, some of which
Ultrasound scan features of nephronophthisis. Renal
or are associated with mutations in NPHP genes
Syndromes which may exhibit nephronophthisis
Joubert syndrome and
Cerebellar vermis aplasia/
kidneys and postaxial
Liver fibrosis, biliary duct
or conorenal syndrome
Jeune syndrome or
Sensenbrenner syndrome or
Ellis van Creveld
Retinal dystrophy, hearing
impairment, obesity, type 2
RJ Simms et al
European Journal of Human Genetics
Nephronophthisis and disease associations
Many disorders have been described in which NPHP is a
clinical feature. Such multisystem features and pleiotropy
are typical of ‘ciliopathies’ such as NPHP. Extrarenal
manifestations are seen in 10–20% of cases of NPHP.12
Here retinal dysplasia and degeneration (also known as
tapetoretinal degeneration or retinitis pigmentosa) may
lead to early and severe visual loss (within 2 years of age),
resembling Leber’s congenital amaurosis (LCA). Later onset
forms present initially with night blindness, which pro-
gresses to visual loss by the age of 10 years. Diagnosis is
made by performing an electroretinogram, which may
show abnormalities before the physical signs of retinitis
pigmentosa and visual loss. Molecular mechanisms of
blindness are secondary to photoreceptor cell defects
(reviewed in reference13).
Joubert syndrome and related disorders
Joubert syndrome and related disorders (JSRD) are char-
acterized by cerebellar vermis hypoplasia and brainstem
of end-stage renal failure is greater than 5 years of age. NPHP1 mutations account for B25% of cases of NPHP. Infantile NPHP is rare (o1% of cases)
but should be suspected, and the known genes screened, if there are clinical and radiological features suggestive of NPHP and age of end-stage renal
failure is less than 5 years of age. If no mutations are found additional NPHP genes should be screened depending on phenotype and a differential
diagnosis of MCKD, ARPKD and BBS should be considered.
Diagnostic algorithm for NPHP. Where there is clinical or radiological suspicion of NPHP, the NPHP1 gene should be screened first if onset
RJ Simms et al
European Journal of Human Genetics
abnormalities.5Brain imaging (MRI) reveals a characteristic
appearance of the brain stem known as the ‘molar tooth
sign’. Typically an affected child will have an irregular
breathing pattern in the newborn period and often
abnormal eye movements. During infancy hypotonia
develops, with ataxia developing late in childhood. Other
conditions associated with JSRD include CNS anomalies,
ocular coloboma, retinal dystrophy, skeletal defects such as
polydactyly, hepatic fibrosis and cystic dysplastic kidneys
This is characterized by abnormal eye movements, which
include nystagmus and difficulty with saccades (smooth
visual pursuits). The transient inability to perform hor-
izontal gaze eye movements in the first years of life is
referred to as oculomotor apraxia (OMA) type Cogan and is
associated with NPHP gene mutations.14Indeed, OMA may
be a mild form of JSRD, as cerebellar vermis aplasia has
been described in this condition.15
A variety of associated skeletal defects have been reported,
the most frequent are cone-shaped epiphyses.16,17Scoliosis
due to poor muscle tone (as part of a JSRD syndrome) and
polydactyly (postaxial, most commonly) may also occur.
Situs inversus and other structural heart defects (cardiac
ventricular sepal defect) have been reported in association
with infantile NPHP.18,19
Other rare associations
Other syndromes that include NPHP have been described.
These include Ellis van Creveld syndrome,20
dysplasia),21Alstrom syndrome, COACH syndrome, Jeune
syndrome and Arima syndrome (Table 1).
Meckel–Gruber like syndrome
The association of occipital encephalocoele, polydactyly
and ductal proliferation in the portal area of the liver and
cystic kidney dysplasia is known as Meckel–Gruber
syndrome (MKS). Recently, mutations in some of the genes
implicated in NPHP/JSRD have been found in patients with
MKS.18,22–24This broadens the phenotypic spectrum of
diseases associated with NPHP gene defects and implies a
Diagnosis relies on a clinical suspicion of the disorder.
NPHP should initially be investigated non-invasively.
Key features would include:
(i) polyuria and polydipsia, enuresis.
(ii) Complications of renal insufficiency/renal failure
such as nausea, vomiting, itch, fatigue (anaemia),
(iii) Family history of renal disease (autosomal recessive
pattern, consanguineous families)
(i) Blood pressure
(ii) Extrarenal manifestations such as retinal pigmenta-
tion, abnormal eye movements and polydactyly.
(i) Urine dipstick (minimal proteinuria (o0.5g/l) and
minimal haematuria is typical).
(ii) Early morning urine to assess urinary concentration.
(iii) USS of abdomen and kidneys to assess renal size, to
look for corticomedullary cysts, corticomedullary
differentiation, to exclude renal tract dilatation and
to examine for liver fibrosis/splenomegaly.
(iv) MRI scan and full neurological evaluation to assess
cerebellar function if neurological symptoms.
Extra renal manifestations associated with NPHP
Isolated oculomotor apraxia
Cerebellar ataxia with vermis hypoplasia
Elevation of hepatic enzymes
Fibrosis, biliary duct proliferation
Phalangeal cone-shaped epiphyses
RJ Simms et al
European Journal of Human Genetics
(v) A baseline ophthalmological examination is essential
to look for minor degrees of coloboma, retinopathy,
OMA. Visual evoked potential studies may be per-
formed in newborn children. ERG studies may be
performed from 8 months of age.
(vi) Blood tests: renal function (urea, creatinine), liver
function (albumin, transaminases, bilirubin), full
blood count (to look for renal anaemia) and clotting
studies (prothrombin time as a marker of liver
function and before renal biopsy, if necessary). If
renal failure is advanced, screening for renal osteody-
strophy, hyperparathyroidism and metabolic acidosis
should be performed.
ling, homozygous or heterozygous NPHP1 deletion (found
in around 25% of cases) can be screened easily by PCR.
Other NPHP genes may be tested by direct sequencing (see
http://www.orpha.net for a list of laboratories). A renal
biopsy should not be necessary if a molecular genetic
diagnosis can be made. If a molecular diagnosis is not
available, a renal biopsy may be required to confirm or
exclude NPHP (Figure 2).
Following appropriate genetic counsel-
ESRF and disease management
(renal replacement therapy) and consideration for renal
transplantation should be undertaken during subsequent
reviews of the patient, once a diagnosis has been made.
NPHP does not recur in transplanted kidneys. Living-
related kidney donation from unaffected family members,
including heterozygous carriers (eg parents), is possible
following clinical evaluation. Referral to the Joubert
Syndrome Foundation (http://www.joubertsyndrome.org/)
and other support organizations for families of children
with disabilities (eg http://www.cafamily.org.uk/services.
html or http://www.orpha.net) may be appropriate.
Preparation for ESRF
Differential diagnosis of NPHP
NPHP should not be confused with autosomal dominant
polycystic kidney disease (ADPKD) which is characterized
by bilateral, multiple renal cysts resulting in kidney
enlargement over time, with extrarenal manifestations
which include simple liver cysts, which arise from the
NPHP should be distinguished from medullary cystic
kidney disease (MCKD), which shares pathological appear-
ances at the macroscopic and microscopic level. However,
unlike NPHP, MCKD is inherited in an autosomal domi-
nant pattern, and the age of ESRF is usually later. Two
different variants of MCKD are known, MCKD1 (gene
remains unidentified) and MCKD2 (secondary to UMOD
mutations), with a median onset of ESRD at 62 and 32
years,25respectively. In contrast to NPHP, the only extra-
renal manifestation of MCKD is the occurrence of hyper-
uricaemia and gout.25
Given the antenatal/early childhood onset of renal
disease in infantile NPHP, care must be taken to exclude
autosomal recessive polycystic kidney disease (ARPKD;
Figure 2). Like NPHP, ARPKD may present at a wide age
distribution, from antenatally to adulthood. Antenatal
ultrasound scanning may reveal markedly enlarged kid-
neys with increased echogencity. Kidney microcysts and
fusiform dilation of collecting ducts are typical of ARPKD.
Liver involvement is always present in ARPKD and may be
the predominant clinical feature, with dilated intrahepatic
bile ducts, liver fibrosis and portal hypertension. The gene
defect is in the PKHD1 gene, encoding its protein product
fibrocystin (or polyductin).26
Finally, Bardet–Biedl syndrome (BBS) must be considered
in the differential diagnosis of NPHP (Figure 2). BBS is
another ciliopathy affecting multiple organ systems.27
Clinical features may include obesity, learning difficulties,
genitourinary tract malformations and limb deformities.28
Renal lesions may include renal cysts, dysplasia, concen-
trating defects and progressive renal failure.28Histologi-
cally, cystic dilatation of the renal collecting ducts have
been described,29reminiscent of infantile NPHP.
Molecular and genetic basis of NPHP
There are a growing number of genes implicated in NPHP.
These will be briefly reviewed in terms of their phenotype,
frequency and most common disease associations. NPHP is
largely inherited as an autosomal recessive disease with
homozygous single gene mutations/deletions or com-
pound heterozygous mutations occurring in a single NPHP
gene. This usually allows a molecular diagnosis and
accurate genetic counselling to be performed. However
oligogenicity, where allelic variants at multiple loci con-
tribute to disease, has been documented for NPHP.30
Likewise, additional NPHP gene mutations may modulate
the phenotype in an epistatic way.31Thus a wide spectrum
of clinical variants with any mutant gene(s) is possible
(Table 3). The encoded NPHP proteins, called nephro-
cystins, typically posses multiple domains (Figure 3).
NPHP1 and nephrocystin-1
NPHP1 was the first NPHP gene identified, using positional
cloning strategies in consanguineous families.32,33Homo-
zygous deletions of B250kb DNA in the region 2q13 are
the most frequent genetic abnormality found.34Other
mutations include compound heterozygosity for the
NPHP1 gene deletion combined with a single point
mutation in the NPHP1 gene. NPHP1 mutations account
for about 25% of cases of NPHP. NPHP1 mutations may be
associated with congenital OMA type Cogan14and Senior–
Loken syndrome35and also give rise to JSRD pheno-
RJ Simms et al
European Journal of Human Genetics
NPHP1 encodes a protein product named nephrocystin-
1. Nephrocystin-1 has been localized to the primary renal
cilium19and to epithelia cell adherens junctions.37,38More
recently, the primary cilial localization has been refined to
the transition zone (at the ciliary base) in renal and
respiratory epithelia and to the connecting cilia in
photoreceptor cells.39Targeting of nephrocystin-1 to the
transition zone of the cilia is dependent on casein kinase 2
phosphorylationand an interaction
Nephrocystin-1 also interacts with other nephrocystins
(Nephrocystin-2, -3, -4 and Jouberin16,41–44) and there is
evidence that this complex of proteins may function in
multiple intracellular locations including the cilium, cell–
cell adherens junctions and at focal adhesions.19,37,38,44,45
Within the human kidney nephrocystin-1 is expressed in
renal collecting ducts.44
INVS/NPHP2 and inversin
Mutations in INVS/NPHP2 give rise to infantile NPHP.19
These mutations are rare and account for o1% of all cases
of NPHP worldwide. The gene encodes the protein named
inversin, which has a dynamic distribution during cell
cycle46and is expressed in renal cilia.19,46,47INVS muta-
tions may cause situs inversus in affected patients, and
knockout animals mimic the human disease, with large
cystic kidneys at an early age, situs inversus and hepato-
biliary malformations.48Retinitis pigmentosa is an un-
common but reported association with INVS mutations.49
Inversin seems to play a crucial role in Wnt signalling,
acting as a switch between canonical and non-canonical
Wnt signalling pathways50,51and is required for conver-
gent extension movements.50This suggests that inversin
plays a role in the developing nephron and in maintenance
of the tubular architecture. This coordinated ability of
epithelial cells to divide and reorganize themselves to form
and maintain tubular structures relies on planar cell
polarity (PCP) signalling. PCP signalling is mediated via
proteins associated with the primary cilia/basal body
complex, such as inversin50and its disruption may under-
lie the pathophysiology of cyst development.51
NPHP3 and nephrocystin-3
Mutations in NPHP3 can produce diverse phenotypes.
Mutations were originally identified in a large Venezuelan
kindred who exhibited NPHP.16Mutations in NPHP3 were
associated with hepatic fibrosis and retinal degeneration in
some affected individuals.16Recently the phenotype of
NPHP3 mutations has been expanded to include Meckel–
Gruber like syndrome.18
NPHP3 encodes nephrocystin-3, which interacts with
nephrocystin-116and inversin,18and can inhibit canonical
Wnt signalling. A mouse model of NPHP type 3, named
pcy, displays cystic kidney disease which responds to
treatment with the aquaretic agents/vasopressin-2-receptor
NPHP4 and nephrocystin-4 (alias nephroretinin)
NPHP4 encodes nephrocystin-4 (alias nephroretinin), a
highly conserved protein which interacts with nephro-
cystin-1.42Nephrocytsin-4 complexes with a-tubulin and
localizes to the primary cilium and basal bodies.41NPHP4
mutations may cause isolated NPHP, NPHP with RP and
NPHP with OMA.53Recently, nephrocystin-4 has been
reported to interact with RPGRIP1L.24,54
NPHP5 and nephrocystin-5
The NPHP5/IQCB1 gene encodes nephrocystin-5. This
protein contains two IQ calmodulin binding sites, which
nephrocystin-5 interacts directly with calmodulin via its
Genetics defects underlying NPHP, associated features and other clinical phenotypes
Gene (protein)Chromosome NPHP typeClinical features associated with NPHP
Mild JS, mild RP, Cogan
RP, liver fibrosis, situs inversus,
Liver fibrosis, RP, situs inversus
NPHP3 (nephrocystin-3)3q22NPHP, Infantile
NPHP4 (nephrocystin-4 or
JS, severe RPIsolated RP, JS, MKS,
AHI1 (Jouberin/AHI1)6q23JS, RPJS
JS, Joubert syndrome type B; RP, retinitis pigmentosa; Cogan, oculomotor apraxia type Cogan; MKS, Meckel–Gruber syndrome; VSD, ventricular
RJ Simms et al
European Journal of Human Genetics
IQ domains, with which it colocalizes to the primary
cilium, and forms a complex with RPGR.55The clinical
phenotype of NPHP5 mutations is always associated with
severe retinal degeneration (early onset Senior–Loken
NPHP6/CEP290 and nephrocystin-6
The NPHP6 (alias CEP290) gene encodes the nephrocystin-
6 protein. Mutations in NPHP6 account for a growing
spectrum of clinical phenotypes which include isolated
NPHP, Senior–Loken syndrome, JSRD,56,57MKS22,23and
variety of protein domains and no common pattern can be identified. Nephrocystin-1, encoded by NPHP1, is a 732 amino acid (aa) protein, which
possesses an N-terminal coiled-coil domain (CC) and a Src-homology 3 domain (SH3). Nephrocystin-2 (alias inversin), encoded by NPHP2/INVS, is a
1260 aa protein with 16 tandem ankyrin repeats, two IQ calmodulin binding domains (IQ). There are two destruction-box (D-box) regions (the first of
which is Apc2 binding) and a bipartite nuclear localization signal (b-NLS) and a putative coiled-coil (CC) domain. Nephrocystin-3, encoded by NPHP3,
is a 1330 aa protein, with a coiled-coil domain (CC), a tetratricopeptide-repeat domain (TPR) and a tubulin tyrosine ligase domain (TTL). Within the
TTL a STAND (signal transduction ATPases with numerous domains) domain, which may be found in P-loop NTPases, is located. Nephrocystin-4 (alias
nephroretinin), encoded by NPHP4 is a 1426 aa protein, which lacks any known domains. There is a central proline rich region. Nephrocystin-5,
encoded by NPHP5/IQCB1 is a 598 aa protein. This protein possesses two IQ calmodulin binding sites, which surround a putative coiled-coil (CC)
domain. Nephrocystin-6 (alias CEP290) is encoded by NPHP6/CEP290. This is a 2479 aa protein with multiple domains which include 13 coiled-coil
(CC) domains; 3 tropomyosin homology domains (TM); 6 RepA/Repþprotein KID motifs (KID); a bipartite nuclear localization signal (b-NLS); a ATP/
GTP-binding site motif A (p-loop). The extent of homology with Structural Maintenance of Chromosomes proteins (SMC) is also indicated. AHI1 (alias
Jouberin) is encoded by AHI1 and is an 1196 aa protein, which contains a Src-homology 3 domain (SH3), 6 WD40 domains (WD40) and an N-terminal
coiled-coil domain. GLIS family zinc finger 2 (alias nephrocystin-7) is a 524 aa protein encoded by GLIS2. It contains 5 zinc finger domains (ZnF).
RPGRIP1L (alias nephrocystin-8) is a 1315 aa protein encoded by RPGRIP1L. Protein domains include 6 coiled-coil (CC) domains and two protein kinase
C conserved region 2 (C2) domains. The C-terminal C2 domain mediates the interaction with nephrocystin-4. NEK8 (alias nephrocystin-9) is a 692 aa
protein with a serine/threonine protein kinases, catalytic domain (S-TKc) and a regulator of chromosome condensation (RCC1) domain, which is
highly conserved throughout evolution.
Nephrocystin proteins and their protein domains. Domain structure of the nephrocystin proteins. Nephrocystin proteins contain a diverse
RJ Simms et al
European Journal of Human Genetics
BBS.58Mutations in NPHP6 have also been described in
21% patients with isolated LCA, making this the most
common gene defect for isolated LCA.59A mouse model,
named rd16 has an in-frame deletion in Nphp6/Cep290 and
mimics this phenotype, with early onset retinal degenera-
tion, but no kidney or brain disease. Nephrocystin-6
directly interacts with and activates the cAMP related
transcription factor, CREB2 (alias ATF4).56Interestingly,
single heterozygous mutations in NPHP6 have been
described in individuals with NPHP who have NPHP1
homozygous deletions.31Similarly, a heterozygous non-
sense mutation in NPHP6 was described together with a
heterozygous NPHP4 missense mutation in an individual
affected with Senior–Loken syndrome.57This tendency
towards digenic and oligogenicity has recently been
reported for other NPHP genes.30,60
NPHP7/GLIS2 and GLIS2
The NPHP7/GLIS2 gene encodes the Kruppel-like zinc-
finger transcription factor GLIS2 that localizes to both the
primary cilia and the nucleus.61Mutations were reported
in a consanguineous Oji-Cree Canadian family with
affected members having isolated NPHP and early onset
renal failure (by 8 years of age) but remains a rare genetic
cause of NPHP.61
A mouse model of targeted Glis2
disruption within the kidney reveals increased rates of
apoptosis, with tubular atrophy and fibrosis.
NPHP8/RPGRIP1L and RPGRIP1L
The RPGRIP1L gene encodes a protein named retinitis
pigmentosa GTPase regulator interacting protein 1-like
protein (RPGRIP1L). Mutations were initially reported in
fetuses affected with MKS and patients with JSRD.24,62
Additional features in some patients included scoliosis,
polydactyly, pituitary agenesis and partial growth hormone
deficiency, reminiscent of RHYNS syndrome.62Regarding
RPGRIP1L mutations, some phenotype–genotype correla-
tions can be drawn as homozygous truncating mutations
seem to cause MKS24,62whereas a heterozygous truncating
mutation or a homozygous missense mutation causes
JSRD. RPGRIP1L is a centrosomal protein, which interacts
with nephrocystin-4. JSRD causing mutations in RPGRIP1L
confer loss off interaction with nephrocystin-4.24
A mouse model Ftm?/? (Fantom or fused-toe mouse)
represents inactivation of the mouse ortholog Rpgrip1l
(Ftm) and recapitulates the cerebral, renal and hepatic
defects of JSRD and MKS.
NPHP9/NEK8 and NEK8
The NEK8 gene encodes the NEK8 protein (never in mitosis
A-related kinase 8). Mutations have been described in two
families with NPHP and one consanguineous family with
infantile NPHP. In one NPHP family with a homo-
zygous NPHP5 mutation, which accounts for the disease
phenotype, a single heterozygous NEK8 mutation was
found.60These findings demonstrate firstly, the rarity of
NEK8 mutations and secondly, that NEK8 mutations may
contribute to oligogenicity in patients with NPHP. The jck
mouse model of cystic kidney disease contains a missense
mutation (G448V) in Nek8. Nek8 and polycystin-2 form a
protein complex together, which adds weight to the
argument that there are common mechanisms underlying
NPHP and ADPKD.63,64
AHI1 and AHI1/Jouberin protein
The AHI1 (Abelson helper integration site 1) gene encodes the
AHI1 protein, which is also known as Jouberin. Mutations
in AHI1 were initially described in individuals with a JSRD
phenotype, with no renal disease.65,66Subsequently, AHI1
mutations were found in individuals with NPHP67and
with retinal degeneration.68
adherens junctions, basal bodies and primary cilia.69
Jouberin interacts with nephrocystin-1, and has been
localized to the renal collecting duct.69
Jouberin is localized to
Other NPHP genes
NPHP1 gene mutations account for around 25% of all cases
of NPHP. The remaining nine genes are each found in
0.05–3% of cases, and collectively probably only account
for another 25% of cases of NPHP, meaning that many
cases remain ‘unsolved’. For JSRD, at least two additional
loci have been reported. These are JBTS1 on chromosome
9q3470and JBTS2 (CORS2) on chromosome 11 (a large
pericentromeric region).71Patients linked to the JBTS2
locus often have renal disease as part of their disease
spectrum. Very recently, mutations in ARL13B, which
encodes a cilial protein, were found in patients with
classical JS, with no renal phenotype.72
The role of the primary cilia in NPHP
The identification of genetic causes of NPHP has high-
lighted the paradigm, that all protein products of cystic
kidney diseases are expressed in the primary renal cilium/
basal body complex.73The primary cilium is present on
nearly every cell in the human body and is a cell surface
projection which acts as an ‘antenna’. This organelle
extends from the basal body and consists of an axoneme
comprising nine microtubular doublets. Assembly of the
axoneme occurs via a process called IFT where proteins are
moved up and down the cilium.73Nephrocystins are
located within this cilial subcellular domain, where they
form complexes with themselves and other related pro-
teins, probably to facilitate signalling cascades. Primary
cilia are thought to sense tubular luminal flow (of urine)
and regulate calcium entry (mediated by polycystin-2
channels).74Nephrocystins are expressed in the connect-
ing cilium of the photoreceptor cell of the retina and
defects here correlate with retinal defects and degenera-
tion, often associated with NPHP gene mutations. Related
RJ Simms et al
European Journal of Human Genetics
syndromes such as Jeune syndrome and Ellis van Creveld
syndrome (EVC) have held true to the cilial paradigm.
Jeune syndrome is secondary to mutations in the IFT
protein IFT8075and EVC (together with EVC2) mutations
underlie EVC, and encodes a cilial/basal body protein.76
Clinical work up (see ‘diagnostic approaches’ section
for details of initial evaluation)
Surveillance and management
disease NPHP is often being managed in the context
of extra-renal manifestations, ongoing surveillance of
affected patients by appropriate specialists is important.
Given that the renal
Patients with NPHP will invariably progress to end-stage
renal failure. Management in a ‘low clearance’ setting is
appropriate to allow time for consideration of renal
replacement therapies. USS scans may detect renal cystic
changes as the disease progresses. Growth, endocrine and
sexual maturation and neurological evaluations should be
regularly performed. Retinal disease may become progres-
sive. Annual eye examinations commencing at the time
of diagnosis is recommended.5Liver function tests should
be performed regularly and liver ultrasound scan should
be performed if suspicion of liver disease.
Genetic testing for NPHP
NPHP is a genetically heterogeneous disorder, however
testing for the most common gene defect, a homozygous
deletion of NPHP1 (Figure 2), is readily available (see http://
www.ukgtn.nhs.uk/gtn/Home; http://www.orpha.net and
http://www.genetests.org/). Direct sequencing of other
NPHP genes may also be performed (see http://autozygosity.
org/diagnostic; http://www.renalgenes.org/ and http://www.
orpha.net). Technologies are however changing rapidly and
given that the genomic regions covered by all known NPHP
genes is less than 1mb (Table 4) a gene capture service
followed by use of high throughput sequencing platforms
may allow an efficient way of screening patients with NPHP
in the near future. Indeed, with the recent descriptions of
oligogenicity30and epistasis31in NPHP, testing of all NPHP
associated genes may be important to understand this
formed before appropriate consent and genetic counsel-
ling. NPHP is inherited in an autosomal recessive manner,
however in some affected individuals more than one
associated gene may contribute to disease.30Such oligo-
genicity has also been reported in BBS.77In general, NPHP
is a moderately severe disorder with major impacts on renal
function and other aspects of health and development. The
variable severity of the disorder in different families and
Genetic testing should not be per-
even between individuals within families makes predicting
of NPHP, prenatal testing is possible. Prenatal imaging may
reveal cystic kidney disease and other abnormalities (such
as structural CNS lesions and polydactyly) in at-risk
pregnancies. INVS/NPHP2 mutations typically produce a
prenatal cystic phenotype, as may the genes which have
been reported to give a MKS-like phenotype (Table 3).
For families with a genetic diagnosis
Treatment and care
treatments for NPHP. Treatment must centre on the
progressive renal failure, which leads to ESRF and the need
for dialysis and transplantation. Potential treatments,
targeted towards the collecting duct may be available for
future use. These include vasopressin V2 receptor antago-
nists, which may alter cystogenesis and progression of
disease. The pcy mouse model of NPHP type 3 responded to
treatment with OPC31260.52Evidence is also growing for
use of rapamycin, an mTOR inhibitor, for reducing renal
At present there are no proven
During the past decade significant insight has been made
in the molecular genetics of NPHP. This disease has moved
from being a pathological description to an inherited
ciliopathy, whereby the most common form may be readily
detected by gene testing, without the need for a renal
biopsy. Additional genes will no doubt be found, and high
throughput technologies show promise for providing a
screen of all currently known genes implicated in cilio-
pathies. The major challenge remains to understand the
biological function of nephrocystin proteins, the molecu-
lar mechanisms that lead to renal failure and the potential
treatments, which may prevent or reverse these changes. In
practical terms, NPHP must be considered among the
length in NPHP genes
Coding exon numbers and genomic sequence
Gene Coding exonsGenomic DNA (bp)
RJ Simms et al
European Journal of Human Genetics
differential diagnosis of any cause of renal failure of
unknown origin. The recognition that NPHP is part of a
ciliopathy, with a wide clinical spectrum of disease will
allow earlier diagnosis to be made, allowing for time for
genetic counselling, appropriate genetic testing and im-
proved treatment planning for ESRF.
RJS is funded by a Mason Medical Research Fellowship. JAS is funded
by GlaxoSmithKline (Clinician Scientist Award).
1 Hildebrandt F, Zhou W: Nephronophthisis-associated cilio-
pathies. J Am Soc Nephrol 2007; 18: 1855–1871.
2 Zollinger HU, Mihatsch MJ, Edefonti A, Gaboardi F, Imbasciati E,
Lennert T: Nephronophthisis (medullary cystic disease of the
kidney). A study using electron microscopy, immunofluores-
cence, and a review of the morphological findings. Helv Paediatr
Acta 1980; 35: 509–530.
3 Krishnan R, Eley L, Sayer JA: Urinary concentration defects and
mechanisms underlying nephronophthisis. Kidney Blood Press Res
2008; 31: 152–162.
4 Gagnadoux MF, Bacri JL, Broyer M, Habib R: Infantile chronic
tubulo-interstitial nephritis with cortical microcysts: variant of
nephronophthisis or new disease entity? Pediatr Nephrol 1989; 3:
5 Parisi MA, Doherty D, Chance PF, Glass IA: Joubert syndrome
(and related disorders) (OMIM 213300). Eur J Hum Genet 2007; 15:
6 Waldherr R, Lennert T, Weber HP, Fodisch HJ, Scharer K: The
nephronophthisis complex. A clinicopathologic study in chil-
dren. Virchows Arch A Pathol Anat Histol 1982; 394: 235–254.
7 Potter DE, Holliday MA, Piel CF, Feduska NJ, Belzer FO, Salvatierra
Jr O: Treatment of end-stage renal disease in children: a 15-year
experience. Kidney Int 1980; 18: 103–109.
8 Ala-Mello S, Sankila EM, Koskimies O, de la Chapelle A,
Ka ¨a ¨ria ¨inen H: Molecular studies in Finnish patients with familial
juvenile nephronophthisis exclude a founder effect and support a
common mutation causing mechanism. J Med Genet 1998; 35:
9 Bollee G, Fakhouri F, Karras A et al: Nephronophthisis related to
homozygous NPHP1 gene deletion as a cause of chronic renal
failure in adults. Nephrol Dial Transplant 2006; 21: 2660–2663.
10 Haider NB, Carmi R, Shalev H, Sheffield VC, Landau D: A Bedouin
kindred with infantile nephronophthisis demonstrates linkage to
chromosome 9 by homozygosity mapping. Am J Hum Genet 1998;
11 Aguilera A, Rivera M, Gallego N, Nogueira J, Ortuno J:
Sonographic appearance of the juvenile nephronophthisis-
cystic renal medulla complex. Nephrol Dial Transplant 1997; 12:
12 Salomon R, Saunier S, Niaudet P: Nephronophthisis. Pediatr
Nephrol 2008 [Epub ahead of print].
13 Adams NA, Awadein A, Toma HS: The retinal ciliopathies.
Ophthalmic Genet 2007; 28: 113–125.
14 Betz R, Rensing C, Otto E et al: Children with ocular motor
apraxia type Cogan carry deletions in the gene (NPHP1) for
juvenile nephronophthisis. J Pediatr 2000; 136: 828–831.
15 Harris CM, Hodgkins PR, Kriss A et al: Familial congenital saccade
initiation failure and isolated cerebellar vermis hypoplasia. Dev
Med Child Neurol 1998; 40: 775–779.
16 Olbrich H, Fliegauf M, Hoefele J et al: Mutations in a novel gene,
NPHP3, cause adolescent nephronophthisis, tapeto-retinal de-
generation and hepatic fibrosis. Nat Genet 2003; 34: 455–459.
17 Ellis DS, Heckenlively JR, Martin CL, Lachman RS, Sakati NA,
Rimoin DL: Leber’s congenital amaurosis associated with familial
juvenile nephronophthisis and cone-shaped epiphyses of the
hands (the Saldino-Mainzer syndrome). Am J Ophthalmol 1984;
18 Bergmann C, Fliegauf M, Bruchle NO et al: Loss of nephrocystin-3
function can cause embryonic lethality, Meckel-Gruber-like
syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia.
Am J Hum Genet 2008; 82: 959–970.
19 Otto EA, Schermer B, Obara T et al: Mutations in INVS encoding
inversin cause nephronophthisis type 2, linking renal cystic
disease to the function of primary cilia and left-right axis
determination. Nat Genet 2003; 34: 413–420.
20 Moudgil A, Bagga A, Kamil ES et al: Nephronophthisis asso-
ciated with Ellis-van Creveld syndrome. Pediatr Nephrol 1998; 12:
21 Di Rocco M, Picco P, Arslanian A et al: Retinitis pigmentosa,
hypopituitarism, nephronophthisis, and mild skeletal dysplasia
(RHYNS): a new syndrome? Am J Med Genet 1997; 73: 1–4.
22 Frank V, den Hollander AI, Bruchle NO et al: Mutations of the
CEP290 gene encoding a centrosomal protein cause Meckel-
Gruber syndrome. Hum Mutat 2008; 29: 45–52.
23 Baala L, Audollent S, Martinovic J et al: Pleiotropic effects of
CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J
Hum Genet 2007; 81: 170–179.
24 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.
25 Scolari F, Ghiggeri GM, Amoroso A, Caridi GL, Aridon P: Genetic
heterogeneity for autosomal dominant medullary cystic kidney
disease (ADMCKD). J Am Soc Nephrol 1998; 9: 393A.
26 Ward CJ, Hogan MC, Rossetti S et al: The gene mutated in
autosomal recessive polycystic kidney disease encodes a large,
receptor-like protein. Nat Genet 2002; 30: 259–269.
27 Adams M, Smith UM, Logan CV, Johnson CA: Recent advances in
the molecular pathology, cell biology and genetics of ciliopathies.
J Med Genet 2008; 45: 257–267.
28 Tobin JL, Beales PL: Bardet-Biedl syndrome: beyond the cilium.
Pediatr Nephrol 2007; 22: 926–936.
29 Hurley RM, Dery P, Norady MB, Drummond KN: The renal
lesion of the Laurence-Moon-Biedl syndrome. J Pediatr 1975; 87:
30 Hoefele J, Wolf MT, O’Toole JF et al: Evidence of oligogenic
inheritance in nephronophthisis. J Am Soc Nephrol 2007; 18:
31 Tory K, Lacoste T, Burglen L et al: High NPHP1 and NPHP6
mutation rate in patients with Joubert syndrome and nephro-
nophthisis: potential epistatic effect of NPHP6 and AHI1 muta-
tions in patients with NPHP1 mutations. J Am Soc Nephrol 2007;
32 Antignac C, Arduy CH, Beckmann JS et al: A gene for familial
juvenile nephronophthisis (recessive medullary cystic kidney
disease) maps to chromosome 2p. Nat Genet 1993; 3: 342–345.
33 Hildebrandt F, Otto E, Rensing C et al: A novel gene encoding an
SH3 domain protein is mutated in nephronophthisis type 1. Nat
Genet 1997; 17: 149–153.
34 Konrad M, Saunier S, Calado J, Gubler MC, Broyer M, Antignac C:
Familialjuvenile nephronophthisis. J Mol Med 1998; 76:
35 Otto EA, Helou J, Allen SJ et al: Mutation analysis in nephro-
mapping, CEL I endonuclease cleavage, and direct sequencing.
Hum Mutat 2008; 29: 418–426.
36 Castori M, Valente EM, Donati MA et al: NPHP1 gene deletion is a
rare cause of Joubert syndrome related disorders. J Med Genet
2005; 42: e9.
37 Donaldson JC, Dempsey PJ, Reddy S, Bouton AH, Coffey RJ,
Hanks SK: Crk-associated substrate p130(Cas) interacts with
nephrocystin and both proteins localize to cell-cell contacts of
polarized epithelial cells. Exp Cell Res 2000; 256: 168–178.
RJ Simms et al
European Journal of Human Genetics
38 Benzing T, Gerke P, Hopker K, Hildebrandt F, Kim E, Walz G: Download full-text
Nephrocystin interacts with Pyk2, p130(Cas), and tensin and
triggers phosphorylation of Pyk2. Proc Natl Acad Sci USA 2001; 98:
39 Fliegauf M, Horvath J, von Schnakenburg C et al: Nephrocystin
specifically localizes to the transition zone of renal and
respiratory cilia and photoreceptor connecting cilia. J Am Soc
Nephrol 2006; 17: 2424–2433.
40 Schermer B, Hopker K, Omran H et al: Phosphorylation by casein
kinase 2 induces PACS-1 binding of nephrocystin and targeting to
cilia. EMBO J 2005; 24: 4415–4424.
41 Mollet G, Silbermann F, Delous M, Salomon R, Antignac C, Saunier
S: Characterization of the nephrocystin/nephrocystin-4 complex
and subcellular localization of nephrocystin-4 to primary cilia and
centrosomes. Hum Mol Genet 2005; 14: 645–656.
42 Mollet G, Salomon R, Gribouval O et al: The gene mutated in
juvenile nephronophthisis type 4 encodes a novel protein that
interacts with nephrocystin. Nat Genet 2002; 32: 300–305.
43 Otto E, Hoefele J, Ruf R et al: A gene mutated in nephronophthisis
and retinitis pigmentosa encodes a novel protein, nephroretinin,
conserved in evolution. Am J Hum Genet 2002; 71: 1167–1171.
44 Eley L, Moochhala SH, Simms R, Hildebrandt F, Sayer JA:
Nephrocystin-1 interacts directly with Ack1 and is expressed in
human collecting duct. Biochem Biophys Res Commun 2008; 371:
45 Watnick T, Germino G: From cilia to cyst. Nat Genet 2003; 34:
46 Morgan D, Eley L, Sayer J et al: Expression analyses and
interaction with the anaphase promoting complex protein
Apc2 suggest a role for inversin in primary cilia and involvement
in the cell cycle. Hum Mol Genet 2002; 11: 3345–3350.
47 Eley L, Turnpenny L, Yates LM et al: A perspective on inversin.
Cell Biol Int 2004; 28: 119–124.
48 Phillips CL, Miller KJ, Filson AJ et al: Renal cysts of inv/inv mice
resemble early infantile nephronophthisis. J Am Soc Nephrol 2004;
49 O’Toole JF, Otto E, Frishberg Y, F H: Retinitis pigmentosa and
renal failure in a patient with mutations in inversin. J Am Soc
Nephrol 2004; 15: 215A.
50 Simons M, Gloy J, Ganner A et al: Inversin, the gene product
mutated in nephronophthisis type II, functions as a molecular
switch between Wnt signaling pathways. Nat Genet 2005; 37:
51 Germino GG: Linking cilia to Wnts. Nat Genet 2005; 37: 455–457.
52 Gattone II VH, Wang X, Harris PC, Torres VE: Inhibition of renal
cystic disease development and progression by a vasopressin V2
receptor antagonist. Nat Med 2003; 9: 1323–1326.
53 Hoefele J, Sudbrak R, Reinhardt R et al: Mutational analysis of the
NPHP4 gene in 250 patients with nephronophthisis. Hum Mutat
2005; 25: 411.
54 Arts HH, Doherty D, van Beersum SE et al: Mutations in the
gene encoding the basal body protein RPGRIP1L, a nephro-
cystin-4 interactor, cause Joubert syndrome. Nat Genet 2007; 39:
55 Otto EA, Loeys B, Khanna H et al: Nephrocystin-5, a ciliary IQ
domain protein, is mutated in Senior-Loken syndrome and
interacts with RPGR and calmodulin. Nat Genet 2005; 37: 282–288.
56 Sayer JA, Otto EA, O’Toole JF et al: A novel centrosomal
protein, nephrocystin-6, is mutated in Joubert syndrome and
activates transcription factor ATF4/CREB2. Nat Genet 2006; 38:
57 Helou J, Otto EA, Attanasio M et al: Mutation analysis of NPHP6/
CEP290 in patients with Joubert syndrome and Senior-Loken
syndrome. J Med Genet 2007; 44: 657–663.
58 Leitch CC, Zaghloul NA, Davis EE et al: Hypomorphic mutations
in syndromic encephalocele genes are associated with Bardet-
Biedl syndrome. Nat Genet 2008; 40: 443–448.
59 den Hollander AI, Koenekoop RK, Yzer S et al: Mutations in the
CEP290 (NPHP6) gene are a frequent cause of Leber congenital
amaurosis. Am J Hum Genet 2006; 79: 556–561.
60 Otto EA, Trapp ML, Schultheiss UT, Helou J, Quarmby LM,
Hildebrandt F: NEK8 mutations affect ciliary and centrosomal
localization and may cause nephronophthisis. J Am Soc Nephrol
2008; 19: 587–592.
61 Attanasio M, Uhlenhaut NH, Sousa VH et al: Loss of GLIS2 causes
nephronophthisis in humans and mice by increased apoptosis
and fibrosis. Nat Genet 2007; 39: 1018–1024.
62 Wolf MT, Saunier S, O’Toole JF et al: Mutational analysis of the
RPGRIP1L gene in patients with Joubert syndrome and nephro-
nophthisis. Kidney Int 2007; 72: 1520–1526.
63 Sohara E, Luo Y, Zhang J, Manning DK, Beier DR, Zhou J: Nek8
regulates the expression and localization of polycystin-1 and
polycystin-2. J Am Soc Nephrol 2008; 19: 469–476.
64 Natoli TA, Gareski TC, Dackowski WR et al: Pkd1 and Nek8
mutations affect cell-cell adhesion and cilia in cysts formed
in kidney organ cultures. Am J Physiol Renal Physiol 2008; 294:
65 Ferland RJ, Eyaid W, Collura RV et al: Abnormal cerebellar
development and axonal decussation due to mutations in AHI1
in Joubert syndrome. Nat Genet 2004; 36: 1008–1013.
66 Dixon-Salazar T, Silhavy JL, Marsh SE et al: Mutations in the AHI1
gene, encoding jouberin, cause Joubert syndrome with cortical
polymicrogyria. Am J Hum Genet 2004; 75: 979–987.
67 Utsch B, Sayer JA, Attanasio M et al: Identification of the first
AHI1 gene mutations in nephronophthisis-associated Joubert
syndrome. Pediatr Nephrol 2006; 21: 32–35.
68 Parisi MA, Doherty D, Eckert ML et al: AHI1 mutations cause both
retinal dystrophy and renal cystic disease in Joubert syndrome.
J Med Genet 2006; 43: 334–339.
69 Eley L, Gabrielides C, Adams M, Johnson CA, Hildebrandt F, Sayer
JA: Jouberin localizes to collecting ducts and interacts with
nephrocystin-1. Kidney Int 2008; 74: 1139–1149.
70 Saar K, Al-Gazali L, Sztriha L et al: Homozygosity mapping in
families with Joubert syndrome identifies a locus on chromosome
9q34.3 and evidence for genetic heterogeneity. Am J Hum Genet
1999; 65: 1666–1671.
71 Valente EM, Salpietro DC, Brancati F et al: Description, nomen-
clature, and mapping of a novel cerebello-renal syndrome with the
molar tooth malformation. Am J Hum Genet 2003; 73: 663–670.
72 Cantagrel V, Silhavy JL, Bielas SL et al: Mutations in the cilia gene
ARL13B lead to the classical form of Joubert syndrome. Am J Hum
Genet 2008; 83: 170–179.
73 Hildebrandt F, Otto E: Cilia and centrosomes: a unifying
pathogenic concept for cystic kidney disease? Nat Rev Genet
2005; 6: 928–940.
74 Nauli SM, Alenghat FJ, Luo Y et al: Polycystins 1 and 2 mediate
mechanosensation in the primary cilium of kidney cells. Nat
Genet 2003; 33: 129–137.
75 Beales PL, Bland E, Tobin JL et al: IFT80, which encodes a
conserved intraflagellar transport protein, is mutated in Jeune
asphyxiating thoracic dystrophy. Nat Genet 2007; 39: 727–729.
76 Ruiz-Perez VL, Blair HJ, Rodriguez-Andres ME et al: Evc is a positive
mediator of Ihh-regulated bone growth that localises at the base of
chondrocyte cilia. Development 2007; 134: 2903–2912.
77 Badano JL, Kim JC, Hoskins BE et al: Heterozygous mutations in
BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-
Biedl patients with two mutations at a second BBS locus. Hum Mol
Genet 2003; 12: 1651–1659.
78 Shillingford JM, Murcia NS, Larson CH et al: The mTOR pathway
is regulated by polycystin-1, and its inhibition reverses renal
cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA
2006; 103: 5466–5471.
79 Tobin JL, Beales PL: Restoration of renal function in zebrafish
models of ciliopathies. Pediatr Nephrol 2008; 23: 2095–2099.
RJ Simms et al
European Journal of Human Genetics