nephronophthisis: disease mechanisms of a ciliopathy

Nephronophthisis: Disease Mechanisms of a Ciliopathy

Friedhelm Hildebrandt,*†‡ Massimo Attanasio,* and Edgar Otto*

Departments of *Pediatrics and †Human Genetics, University of Michigan, and ‡Howard Hughes Medical Institute,Ann Arbor, Michigan

Nephronophthisis (NPHP) is an autoso-mal recessive cystic kidney disease thatconstitutes the most frequent geneticcause for ESRD in the first three decadesof life.1–4 Renal failure manifests at a me-dian age of 13 yr. Initial symptoms are rel-atively mild, start at approximately age 6 yr,and consist of polyuria, polydipsia, sec-ondary enuresis, and anemia.5 Regularfluid intake at nighttime is a characteristicfeature of the patients’ history. Renal ultra-sound reveals normal kidney size, in-creased echogenicity, and corticomedul-lary cysts (Figure 1A).6 Renal histologyexhibits a characteristic triad of cortico-medullary cysts, tubular basement mem-brane disruption, and tubulointerstitialnephropathy (Figure 1B).7,8 Disease recur-rence has never been reported in kidneys

transplanted into patients with NPHP.9

NPHP is inherited in an autosomal reces-sive mode.4 It was first described by Smithand Graham in 19452 and by Fanconi etal.,3 who introduced the term “familial ju-venile nephronophthisis.” In juvenileNPHP, renal failure develops within thefirst three decades of life.10–12 In contrast,infantile NPHP, which is characterized bymutations in NPHP2/inversin, leads to re-nal failure between birth and age 3 yr.12,13

In more than 10% of cases, NPHP is asso-ciated with extrarenal involvement, pri-marily including retinal degeneration (Se-nior-Løken syndrome), cerebellar vermisaplasia (Joubert syndrome), liver fibrosis,and cone-shaped epiphyses. These clinicalfeatures are discussed here in light of thecilia/centrosome theory of NPHP. More

than 300 cases of NPHP have been pub-lished in the literature.7 It has been re-ported from virtually all regions of theworld.14 The incidence of the disease is es-timated at nine patients per 8.3 million15 inthe United States or one in 50,000 livebirths in Canada.7,16 In the North Ameri-can pediatric population with ESRD,pooled data indicate a prevalence of ap-proximately 5% of all children with renalfailure.17,18

Positional cloning has identified ninegenes causing nephronophthisis whenmutated.13,19 –29 These are monogenic re-cessive genes, suggesting that mutationsin each single one is sufficient by itself tocause NPHP in a patient bearing muta-tions and indicating their gene productsare necessary for normal kidney func-tion. Positional cloning generated newinsights into disease mechanisms ofNPHP by revealing the mechanism is re-lated to the signaling pathways of pri-mary cilia, centrosomes, and planar cellpolarity.1,13,30,31 The demonstration thatnephrocystin-1 and inversin/NPHP2 lo-calize to primary cilia of renal tubularcells13 was among the first findings tosupport a new unifying theory of renal

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence: Dr. Friedhelm Hildebrandt,Howard Hughes Medical Institute, Departments ofPediatrics and of Human Genetics, University ofMichigan Health System, 8220C MSRB III, 1150West Medical Center Drive, Ann Arbor, MI 48109-5646. Phone: 734-615-7895; Fax: 734-615-1386;E-mail: [email protected]

Copyright � 2009 by the American Society ofNephrology

ABSTRACTNephronophthisis (NPHP), a recessive cystic kidney disease, is the most frequentgenetic cause of end-stage kidney disease in children and young adults. Positionalcloning of nine genes (NPHP1 through 9) and functional characterization of theirencoded proteins (nephrocystins) have contributed to a unifying theory that definescystic kidney diseases as “ciliopathies.” The theory is based on the finding that allproteins mutated in cystic kidney diseases of humans or animal models are expressedin primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensoryorganelles that connect mechanosensory, visual, and other stimuli to mechanisms ofepithelial cell polarity and cell-cycle control. Mutations in NPHP genes cause defects insignaling mechanisms that involve the noncanonical Wnt signaling pathway and thesonic hedgehog signaling pathway, resulting in defects of planar cell polarity andtissue maintenance. The ciliary theory explains the multiple organ involvement inNPHP, which includes retinal degeneration, cerebellar hypoplasia, liver fibrosis, situsinversus, and mental retardation. Positional cloning of dozens of unknown genes thatcause NPHP will elucidate further signaling mechanisms involved. Nephrocystins arehighly conserved in evolution, thereby allowing the use of animal models to developfuture therapeutic approaches.

J Am Soc Nephrol 20: 23–35, 2009. doi: 10.1681/ASN.2008050456

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J Am Soc Nephrol 20: 23–35, 2009 ISSN : 1046-6673/2001-23 23

cystogenesis.30 This theory states that thecystoproteins mutated32 in renal cysticdisease in humans, mice, or zebrafish areexpressed in primary cilia, basal bodies,or centrosomes.30,33 Basal bodies are thefoundations from which cilia are assem-bled (Figure 2). After mitosis and cell di-vision are completed, basal bodies derivefrom the mother centriole of the centriolepair that had organized the mitotic spin-dle during cell division. As cilia areformed from the basal body, the daughtercentriole is placed on the side of the nu-cleus opposite to the basal body, thusspecifying cell polarity. The structureand function of primary cilia and basalbodies are delineated in Figure 2.

Primary cilia are highly conservedstructures that sense a wide variety of ex-tracellular cues in a wide spectrum of ep-ithelial tissues. There is a broad range ofcues that can be received by specific cili-ary receptors, including photosensation,mechanosensation, osmosensation, andolfactory sensation. In general, thepathogenesis of ciliopathies is based onan inability of epithelial cells to sense orprocess extracellular cues.34

POSITIONAL CLONING REVEALSNEPHRONOPHTHISIS AS A“CILIOPATHY”

By positional cloning, we and othersidentified recessive mutations in ninenovel genes as causing NPHP: NPHP1,19,20

NPHP2/inversin,13 NPHP3,22 NPHP4,21,27

NPHP5,23 NPHP6/CEP290,24,35 NPHP7/GLIS2,28 NPHP8/RPGRIP1L,29,36,37 and

NPHP9/NEK8,38 defining NPHP types 1through 9, respectively. This collectionof genes has made diagnostic testing pos-sible (http://www.renalgenes.org). Ho-mozygous deletions in the NPHP1 geneaccount for approximately 21% of allNPHP cases, whereas the other genescontribute less than 3% each (Figure 3).As determined in more than 1000 fami-lies with NPHP, the causative genes are

Figure 1. Morphology of nephronophthisis. (A) Renal ultrasound demonstrates in-creased echogenicity, loss of corticomedullary differentiation, and the presence of cor-ticomedullary cysts. In contrast to PKD, kidneys are not enlarged. (B) Renal histology inNPHP shows the characteristic triad of renal tubular cysts, tubular membrane disruption,and tubulointerstitial cell infiltrates with interstitial fibrosis and periglomerular fibrosis (Bis courtesy of D. Bockenhauer, London).

Tipcomplex

Ciliaryaxoneme

Ciliarymembrane

Transitionfibers

Basalbody

Nucleus

Centrosome

Eb1

Dynein

Kinesin-2

Pc1/Pc2complex

IFT cargo

Retrogradetransport

Anterogradetransport

IFTcomplexes

AB

Cell membrane

Figure 2. Cilia structure and intraflagellar transport. The cilium is ahair-like structure that extends from the cell surface into the extra-cellular space. Virtually all vertebrate cell types can produce cilia.Cilia consist of a microtubule-based axoneme covered by a special-ized plasma membrane. The axoneme has nine peripheral microtu-bule doublets. There may be two central microtubules (9 � 2 versus9 � 0 axoneme). 9 � 2 cilia usually have dynein arms that link themicrotubule doublets and are motile, whereas most 9 � 0 cilia lackdynein arms and are nonmotile (“primary cilia”) with a few excep-tions. The ciliary axoneme is anchored in the basal body, a micro-tubule-organizing center derived from the mother centriole. Thetransition zone at the junction of the basal body acts as a filter forthe molecules that can pass into or out of the cilium. Nephrocystin-1is localized at the transition zone of epithelial cells.47 During cilio-genesis, cilia elongate from the basal body by the addition of newaxonemal subunits to the distal tip, the plus end of the microtu-bules. Axonemal and membrane components are transported in raftmacromolecular particles (complex A and B) by so-called intraflagel-lar transport (IFT) along the axonemal doublet microtubules.129

Anterograde transport toward the tip is driven by heterotrimerickinesin 2, which contains motor subunits Kif3a and Kif3b and anonmotor subunit. Mutations of Kif3a cause renal cysts and cere-bellar vermis aplasia in mice.130 Retrograde transport back to thecell body occurs via the motor protein cytoplasmic dynein 1B.131

Adapted from Bisgrove and Yost.132


24 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 23–35, 2009

still unknown in approximately 70% ofpatients, indicating that additional genesare involved in the pathogenesis ofNPHP (Figure 3). Evidence has beengenerated that more than one recessivegene may be mutated in individual pa-tients with NPHP, as has been proposedfor the related disorder Bardet-Biedl syn-drome (BBS).39 In this situation, muta-tions in an additional NPHP gene maymodify the clinical picture of NPHP inthe direction of a more severe extrarenalinvolvement.40,41 Here, disease mecha-nisms of NPHP are discussed in the con-text of the discovery of each of the genesencoding NPHP. We describe how re-sulting insights into the function of theirgene products, the nephrocystins, helpedrefine the cilia/centrosome theory of re-nal cystic diseases.

NPHP1 Locates to Cell Contactsand the Cilia Transition ZoneMutations in NPHP1 were identified ascausing juvenile nephronophthisis type1.19,20 NPHP1 encodes nephrocystin-1, aprotein that interacts with components ofcell–cell and cell–matrix signaling, includ-ing p130Cas,42 focal adhesion kinase 2,43

tensin, and filamin A and B.44,45 Nephro-cystin-1 is located at adherens junctionsand focal adhesions of renal epithelialcells,44,45 which are involved in cell–celland cell–basement membrane contacts,respectively (Figure 4). It also interactswith the product of other nephronophthi-sis genes such as nephrocystin-2/inver-sin,13 nephrocystin-3,22 and nephrocystin-4.21,46 More recently, it was shown thatnephrocystin-1 is targeted to the transitionzone of motile and primary cilia by the pro-tein phosphofurin acidic cluster sortingprotein 1 (PACS-1).47 This is initiated bycasein kinase 2–mediated phosphorylationof three critical serine residues within acluster of acidic amino acids in nephrocys-tin, leading to PACS-1 binding and co-lo-calization of nephrocystin with PACS-1 atthe base of cilia.48

When NPHP1 was first identified,19

we proposed a pathogenic hypothesisthat tied nephrocystin-1 in with defectsof cell– cell and cell–matrix signaling.49,50

This was based on the finding thatnephrocystin-1 contains an SH3 do-

main, localizes to adherens junctions andfocal adhesions of renal epithelial cells,and interacts with integral componentsof these structures, such as p130CAS.44,45

This “adherens junction/focal adhesionhypothesis” of NPHP pathogenesis49,50

was partially reconciled with the “cilia/centrosome” hypothesis in an integrativehypothesis by showing that nephrocys-tin-4 in polarized epithelial cells co-lo-calizes with �-catenin at cell– cell contactsites and to primary cilia, whereas, in di-viding cells, it localizes to centrosomes46

(Figure 4).

NPHP2/Inversin Implicates Cilia andPlanar Cell Polarity in CystogenesisOn the basis of positional cloning12 andcandidate gene data,51,52 we identifiedmutations in human inversin (INVS) asthe cause of infantile NPHP (type 2) withand without situs inversus.13 The renalcystic changes of infantile nephronoph-thisis (NPHP type 2) combine clinicalfeatures of NPHP and of polycystic kid-ney disease (PKD).53 We demonstratedthat nephrocystin-1 and NPHP2/inver-sin interact with �-tubulin, which con-stitutes the microtubule axoneme of pri-mary cilia, and that they localize atprimary cilia of renal tubular cells.13 Thiswas one of the first findings to support aunifying theory of renal cystogen-esis1,30,33,54 which states that cystopro-teins, which are mutated in renal cysticdisease in humans, mice, or zebrafish, are

expressed in primary cilia, basal bodies,or centrosomes.13,30 The interaction andco-localization to cilia and basal bodiesof nephrocystin-1, inversin, and �-tubu-lin provide a functional link between thepathogenesis of NPHP, the pathogenesisof PKD, primary cilia function, and left–right axis determination.13 Okada et al.55

previously demonstrated that inversin isneeded to position cilia in cells of theventral node. Inversin was then shown tolocalize to different subcellular locations,in a cell cycle– dependent manner (Fig-ure 5). Specifically, it is found at the mi-totic spindle in mitosis, at the mid-bodyin cytokinesis, and in cilia at the basalbody and centrosome in interphase (Fig-ure 5). All of these subcellular organellesare involved in regulation of planar cellpolarity or the cell cycle (Figure 4).

A major breakthrough was also madein the understanding of the pathogenesisof renal cystic diseases when Simons etal.56 demonstrated a role for inversin/NPHP2 in signaling mechanisms of pla-nar cell polarity necessary to maintainnormal tubular development and mor-phology, as outlined in Figure 6.31,56 As aconsequence of this model, when inver-sin is defective (as in NPHP type 2), ca-nonical Wnt pathway will prevail anddisrupt the apical-basolateral polarity ofrenal epithelium.31 Because planar cellpolarity signaling is important for ori-ented cell division, it seems logical thatFisher et al.57 were able to demonstrate

NPHP21%

NPHP31%

NPHP53%

NPHP61%

NPHP7/ GLIS20.1%

NPHP8/ RPGRIP1L0.5%

NPHP9/ NEK80.1%

No mutation70%

NPHP121%

NPHP42%

Figure 3. Distribution of causative mutations in the NPHP1 through NPHP9 genes in aworldwide cohort of 1079 families with NPHP. Note that whereas mutations in NPHP1account for �21% of NPHP, all other genes are in the range of �3%.

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J Am Soc Nephrol 20: 23–35, 2009 Mechanisms of Nephronophthisis 25

abnormal orientation of mitotic spindlesin two different rodent models of cystickidney disease.

NPHP3: A Doorstep to Treatment?By positional cloning, we identified mu-tations in NPHP3 as responsible for ado-lescent nephronophthisis in a large Ven-ezuelan kindred.11,22 We demonstratedthat mutations in the murine orthologNphp3 cause the renal cystic mouse mu-tant pcy,22 which was demonstrated to beresponsive to treatment with a vasopres-sin receptor antagonist.58 Recently, it wasshown that complete loss of Nphp3 func-tion results in situs inversus, congenitalheart defects, and embryonic lethality inmice.59 In addition, truncating muta-tions of NPHP3 in humans causes abroad clinical spectrum of early embry-onic patterning defects that resemblesMeckel syndrome. This includes situs in-versus, polydactyly, central nervous sys-tem malformations, structural heart de-fects, preauricular fistulae, and a widerange of congenital anomalies of the kid-ney and urinary tract.59

NPHP4 Is Conserved inCaenorhabditis elegansMutations in the novel gene NPHP4were identified by homozygosity map-ping and total genome search for link-age.21,60,61 Nephrocystin-4, like inversin,localizes to primary cilia, basal bodies,centrosomes, and the cortical actin cy-toskeleton46 (Figure 4). Nephrocystin-4is conserved in Caenorhabditis elegansand expressed in ciliated head and tailneurons of the nematode.62 Uponknockdown, it exhibits a male matingphenotype, similar to the phenotypefound upon knockdown of the polycys-tin-1 and polycystin-2 orthologs.62 Lo-calization of nphp-1 and nphp-4 to someof these ciliated neurons also overlapswith localization of the cystoprotein or-thologs polycystin-1 (lov-1), polycys-tin-2 (pkd-2) and with many orthologs ofBBS proteins,62,63 similar to what hasbeen described for lov-1 and pkd-2 mu-tants.64 These data were refined for spe-cific neuronal cell types,65,66 and the ne-cessity of nphp-1 and nphp-4 formorphologic integrity of ciliated neu-

rons in C. elegans was observed.67,68

nphp-4 has an additional role in deter-mining the life span of the worm.69

Evolutionary conservation of cys-toproteins goes even further: Some cys-toproteins have been conserved overmore than 1.5 billion years of evolutionfrom the unicellular organism Chlamy-domonas reinhardtii to vertebrates. Ch.

Reinhardtii uses two motor cilia (flagella)for locomotion. Striking, nephrocystin-4and at least six proteins mutated in BBSare conserved in Ch. reinhardtii, wherethey are part of its basal body pro-teome.63,70 Defects of cystoprotein or-thologs in Ch. reinhardtii have deficientintraflagellar transport and flagellar pro-pulsion.71

1

NEPHROCYSTINS SIGNALING

NPHP1 =

2 =

3 =

4 =

5 =

6 =

7 =

NPHP2/Inversin

NPHP3

NPHP4

NPHP5

NPHP6/CEP290

NPHP7/GLIS2

PKD

Jeune

Nephronophthisis

Bardet-Biedl

MKS

Nucleus

LOCALIZATION CILIOPATHY

Receptor

Adherensjunction

Cargo

Motor protein

Transition zone

Basal body

Golgi

Mitotic spindle

Centrosome(orientation)

PC1,2

IFT80

KIF3A

NPHP1

2-4-5-6-8-9

1–5

Wnt Shh

7

2

1

1

2

PC2

PACS-1

BBS1-12

Joubert

1

BBS1-12

2-4-5-6-8-9

7

8 =

9 =

NPHP8/RPGRIP1L

NPHP9/NEK8

8

8 =

9 =

NPHP8/RPGRIP1L

NPHP9/NEK8

A B C D

Figure 4. Subcellular localization of nephrocystins to primary cilia, basal bodies, themitotic spindle, focal adhesions and adherens junctions, and functional interaction withother proteins mutated in renal “ciliopathies.” “Cystoproteins” are proteins of genesmutated in cystic kidney diseases of humans, mice, or zebrafish. Depending on cell-cyclestage, cystoproteins are localized at different subcellular organelles (shown in gray orbrown),24,133 including primary cilia, basal bodies, endoplasmic reticulum, the mitoticspindle, centrosomes, adherens junctions, or focal adhesions. Arrows in the primarycilium indicate the direction of anterograde transport along the microtubule systemmediated by kinesin-2 and retrograde transport by cytoplasmic dynein 1b. (A) Mostnephrocystins (blue) are located at cilia, the basal body, and centrosome in a cellcycle–dependent manner. NPHP1 is also at the transition zone, focal adhesions, andadherens junctions. (B) Sensory cilia perceive and process cell external signals, and“cystoproteins” are involved in signaling mechanisms downstream of cilial signal recog-nition. Downstream of cilia (pink), Wnt signaling (Figure 6) and hedgehog signaling(Figure 8) play a role in planar cell polarity, which is mediated (C) partially throughorientation of centrosomes and the mitotic spindle poles (Figure 7). (D) Cilia-dependentmechanisms of planar cell polarity seem to be central to the pathogenesis of theciliopathies, the most prominent of which are listed on the right. Wnt, Wnt signalingpathway; Shh, sonic hedgehog signaling pathway.



NPHP5: The Senior-LøkenSyndrome GeneWhen the novel gene NPHP5 was identi-fied as mutated in nephronophthisis type5,23 all mutations detected were trunca-tions of the encoded protein nephrocys-tin-5, and all patients had early-onsetretinitis pigmentosa (Senior-Løken syn-drome). Nephrocystin-5 contains an IQdomain, which directly interacts withcalmodulin,23 and is in a complex withthe retinitis pigmentosa GTPase regula-tor (RPGR), which when defective causesX-linked retinitis pigmentosa. Bothnephrocystin-5 and RPGR are localizedin connecting cilia of photoreceptors andin primary cilia of renal epithelial cells23

(Figure 4). That connecting cilia of pho-toreceptors are the structural equivalentsof primary cilia of renal epithelial cellsrenders an explanation for retinal in-volvement in the retinal-renal syndromeSenior-Løken syndrome.

CYSTOGENESIS: DEFECTIVEREGULATION OF PLANAR CELLPOLARITY?

NPHP6/CEP290: Centrosomes as aCentral Hub for Planar Cell PolarityRegulationWe identified by positional cloning re-cessive, truncating mutations in a novelgene NPHP6/CEP290 as the cause ofNPHP type 6 and Joubert syndrome type5.24 Its gene product nephrocystin-6/Cep29024 is part of the centrosomal pro-teome.24 Like NPHP2/inversin (Figure5) and NPHP4, NPHP6/CEP290 is ex-

pressed in centrosomes and the mitoticspindle in a cell cycle– dependent man-ner. Abrogation of NPHP6 function inzebrafish causes planar cell polarity de-fects and recapitulates the human phe-

notype of NPHP type 6, including renalcysts, retinal degeneration, and cerebel-lar defects.24 Nephrocystin-6 modulatesthe activity of ATF4/CREB2, a transcrip-tion factor implicated in cAMP-depen-

Figure 5. Inversin/NPHP2 localizes to cilia, centrosomes, and the mitotic spindle in a cell cycle–dependent manner. (A) Inversin/NPHP2is found in interphase in the cilial axoneme (data not shown), close to the centrioles of the basal body complex (arrow), and at thecentrosome (arrow head). (B through D) In metaphase (B) and anaphase (C), it is at the mitotic spindle (arrows) and in telophase (D) atthe midbody (arrow) of the separating cells and in the nucleus. This reflects a centriole-associated function of inversin/NPHP2throughout the cell cycle. Reprinted from Morgan et al.,134 with permission.

Nucleus

Basal body

Wnt

Frizzled

Dvl

Dvl Dvl

Dvl

Apc

RhoROK

GSK3β

?

?

Ca2+

?

Inv

Axin

Axin

DvlAxin

Lrp5/6

Wnt

Frizzled

Lrp5/6

β-catenin

β-catenindestruction complex

Proteasomaldegradation

Lef/Tcf

MECHANOSENSORYCILIUM AT REST

MECHANOSENSORYCILIUM BENT BY URINE FLOW

C-MycC-Myc

Dvl

Inv

Inv

Lef/Tcf

A B

FLOW

Figure 6. Inversin/NPHP2 mediates a switch from the canonical the noncanonical Wntsignaling pathway, which plays a role in planar cell polarity maintenance.56 (A) This illustrationof a renal tubular epithelial cell shows how Wnt signaling occurs primarily through �-catenin–dependent pathways in the absence of urine flow. Ligand binding by the frizzled receptorresults in inactivation of the �-catenin destruction complex through the presence of dishev-eled (Dvl), increased �-catenin levels, and upregulation of effector gene expression of thecanonical Wnt signaling pathway. (B) Stimulation of the primary cilium (e.g., by urine flow)results in increased expression of inversin (Inv), which then reduces levels of cytoplasmic Dvlby increasing its proteasomal degradation. This allows reassembly and activation of the�-catenin destruction complex, thereby switching from the canonical to the noncanonicalWnt signaling pathway. The model is consistent with the finding that overexpression of�-catenin (equivalent to canonical Wnt signaling) leads to renal cysts in a mouse model.135

Adapted from Germino.31



dent renal cyst formation.58 Interestingly, a300–amino acid in-frame deletion ofNPHP6/CEP290 causes retinal degenera-tion only, without renal or cerebellar in-volvement in the rds16 mouse model.24

This is in accordance with the recent find-ing that a hypomorphic mutation ofNphp6/Cep290 represents the most fre-quent cause of Leber’s congenital amauro-sis.24 Mutations in NPHP6/CEP290 havebeen confirmed as causing Joubert syn-drome with and without renal involve-ment.35 Furthermore, truncating muta-tions in NPHP6 were shown to causeMeckel-Gruber syndrome.72

Correct orientation of the mitotic spin-dle and centrosomes with respect to thelongitudinal axis of the tubule is critical forproper apical-basolateral polarity (Figure7). Noncanonical Wnt signaling (see Fig-ure 6) is involved in these processes duringrenal tubular morphogenesis, when in ro-dent renal tubules still elongate postnatally.The structure that would result from dis-ruption of the longitudinal growth wouldbe a dilated tubule or cyst. Recently, evi-dence for a role of planar cell polarity inrenal cystic diseases57 was advanced bymeasuring orientation of the mitotic spin-dle through three-dimensional imaging ofrenal tubules. Comparison of the distribu-tion of the mitotic angles in wild-type ani-mals and rodent cystic kidney diseasemodels suggest that mitotic angles of tworodent models of cystic kidneys, theHNF1�-deficient mouse model and thepck rat model, were clearly different fromwild-type littermates.57

NPHP7/GLIS2: The Link toHedgehog SignalingRecently, we identified mutations in thegene NPHP7/GLIS2 in a Cree Indian kin-dred encoding the transcription factorGli-similar protein 2 as the cause ofNPHP type 728 (Figure 4). Starting at 8wk of age, Glis2 mutant mice show severerenal atrophy and fibrosis resemblinghuman nephronophthisis.28 Differentialgene expression studies on Glis2 mutantkidneys demonstrated that genes pro-moting epithelial-to-mesenchymal tran-sition and fibrosis are upregulated in theabsence of Glis2.28 Striking, there wasalso prominent apoptosis present in dis-

tal tubular segments of the kidney, whichmight provide an explanation for whyPKD kidneys are enlarged with hyper-proliferation prevailing, whereas inNPHP, kidney size is reduced. GLIS2 isrelated to the GLI transcription factor,and these findings implicate the hedge-hog pathway in the pathogenesis of cystickidney diseases (Figure 8). It is a signal-ing pathway that controls cell determina-tion and tissue patterning during embry-ogenesis. The other known role of

hedgehog is the maintenance of stem cellpools in postembryonic tissues.

NPHP8: A Clinical Spectrum fromMeckel Syndrome to JoubertSyndromeRecently, missense and truncating muta-tions in the RPGRIP1L gene were identifiedby positional cloning as the cause of a Jou-bert syndrome-like phenotype (cerebro-oculo-renal syndrome [CORS]) andMeckel syndrome (Figure 4).29,36 It was

Mitotic spindle orientationalong the longitudinal axis:

Directional cell division

Disrupted planar orientation:Non-directional cell division,

cyst development

Planarasymmetry

PKD

Figure 7. Defects of cystoproteins lead to disruption of planar cell polarity and thereby torenal cysts through to malorientation of the centrosome or mitotic spindle complex. Correctorientation of the mitotic spindle and centrosomes with respect to the longitudinal axis of thetubule is critical for proper planar cell polarity (i.e., the orientation of an epithelial cell layer inthree-dimensional space). Noncanonical Wnt signaling (see Figure 6) is involved in regulationof planar cell polarity during renal tubular morphogenesis; in rodents 2 wk post partum, thetubules still elongate. The structure that would result from disruption of this longitudinalorientation is a dilated tubule or cyst. Adapted from Germino.31

Cilium

Gli1 Gli2

GliAct

Gli3

Gli3R

PKA

PromoteGli3

processingPlasmamembrane

Ptch1

Intracellularvesicle

Smo

Cos2 ?

Sufu

Iguana

Cilium

Gli1 Gli2

GliAct

Gli3

Gli3R

PKA

Ptch1

Smo

Cos2

Sufu

Iguana

Hedgehog

Figure 8. The hedgehog signaling pathway may be involved in renal cystogenesis. Inthe hedgehog pathway of vertebrates, upon binding of the Shh ligand to the patched(Ptch1) receptor, repression of the smoothened (Smo) receptor to be inserted into thecilium membrane is relieved, and posttranslational modification of the Gli transcriptionfactors within the cilium induces both their activator (GliAct) and repressor (GliR) functions.Several studies in mice have demonstrated that ciliary proteins are needed for hedgehogsignaling. Recently, the related transcription factor Gli-similar 2 (GLIS2) was found to bemutated in NPHP type 7. Adapted from Huangfu and Anderson.136



shown that defects in the mouse orthologRpgrip1l (Ftm) recapitulate the cerebral,renal, and hepatic defects of CORS andMeckel syndrome. RPGRIP1L co-localizesat the basal body and centrosomes with theprotein products of both NPHP6 andNPHP4.29 RPGRIP1L missense mutationsfound in individuals with CORS diminishthe interaction between RPGRIP1L andnephrocystin-4. Missense mutations wereseen in patients with Joubert syndrome.29,36

These findings confirmed there is a contin-uum for the multiorgan phenotypic abnor-malities found in Meckel syndrome, Joubertsyndrome/CORS, and nephronophthisison the basis of distinct mutations of iden-tical genes (multiple allelism).

NPHP9: The Link From Cilia to Cell-Cycle ControlWe recently identified three differenthighly conserved amino acid changes inthe gene NEK8 (never in mitosis kinase 8)as causing NPHP type 9.73 One of the mu-tations identified is positioned in the sameRCC1 domain in which a missense muta-tion causes renal cystic disease in jckmice.74,75 Upon expression in medullarycollecting duct cells, all three mutant formsof NEK8 showed defects in ciliary and cen-trosomal localization to varying degrees,supporting the notion that mutations inNEK8 cause NPHP type 938 (Figure 4). AsNEK8 plays a major role in cell-cycle regu-lation, these findings provide a direct linkbetween a protein defective in renal cysticdisease and the role of centrosomes for cell-cycle regulation (Figure 4). In this contextit is interesting that also for polycystin-1and -2 signaling, the renal cystic phenotypehas been linked to cell growth regulation.Polycystin-1 expression activates the JAK-STAT pathway, thereby upregulatingp21(waf1) and inducing cell-cycle arrest inG0/G1.76 Cell-cycle arrest required poly-cystin-2. Involvement of polycystin-1 and-2 signaling in the JAK/STAT pathwaymight explain how mutations of eithergene can result in dysregulated growth.76

Involvement of cell-cycle regulation in re-nal cystic disease was confirmed by dem-onstration that two mouse models of PKD(jck and cpk) can be efficiently treated withthe cyclin-dependent kinase inhibitorroscovitine.77

THE CILIARY THEORY EXPLAINSEXTRARENAL INVOLVEMENT OFEYE, BRAIN, AND LIVER IN NPHP

A prominent feature of NPHP is in-volvement of multiple organs (pleiot-ropy) outside the kidney. Defects inother organs are usually of a degenera-tive or developmental nature (Figure9). Specifically, NPHP may be associ-ated with tapetoretinal degeneration(Senior-Løken syndrome78,79), cere-bellar vermis aplasia (Joubert syn-drome80,81), ocular motor apraxia typeCogan,82 mental retardation,24 liver fi-brosis,83 or cone-shaped epiphyses ofthe phalanges (Mainzer-Saldino syn-drome84). Infantile NPHP type 213 canbe associated with situs inversus,13 reti-nitis pigmentosa,85 or cardiac ven-

tricular septal defect.13 In some in-stances, there seems to be a genotype/phenotype correlation regardingpleiotropy. For instance, there is in-volvement of the retina in all knowncases with mutations of NPHP5 orNPHP6. In other instances, such asNPHP1 mutations, the molecular basisof eye involvement is unknown. Thepleiotropy of NPHP has now found apotential explanation in the ciliary hy-pothesis of cystic kidney diseases (Fig-ure 9). The extrarenal organ involve-ment in NPHP is discussed by organsystem as follows (Figure 9).

Retinal Involvement (Senior-LøkenSyndrome)The renal-retinal involvement in Senior-Løken syndrome can be explained by the

Figure 9. Ciliopathies feature a broad spectrum of organ involvement, shown herefor the nephronophthisis-related ciliopathies. There is overlap between differentsyndromes: Exclusive kidney involvement is called nephronophthisis. Associatedretinal degeneration in known as Senior-Løken syndrome. Involvement of the cere-bellum represents Joubert syndrome. In the most severe form, Meckel syndrome,brain malformations, liver fibrosis, heart defects, polydactyly, and perinatal mortalityare associated. It has recently become evident that the spectrum can vary by at leasttwo mechanisms: First, multiple allelism, in which a hypomorphic mutation may causea milder phenotype. For example, a splice site mutation of NPHP6 may cause Lebercongenital optical atrophy (LCA) only. In another example, the presence of onenontruncating mutation in NPHP8 can rescue the phenotype from Meckel syndrometo Joubert syndrome. Second, NPHP genes can modify each other. For instance,NPHP6 and AHI1 modify recessive NPHP1 mutations to express a more severephenotype.137



fact that the primary cilium of renal epi-thelial cells is a structural equivalent ofthe connecting cilium of photoreceptorcells in the retina.86 We have shown thatnephrocystin-5 and nephrocystin-6 areexpressed in the connecting cilia of pho-toreceptors.72,87

Cerebellar Vermis Aplasia (JoubertSyndrome)In Joubert syndrome, NPHP is associ-ated with coloboma of the eye, with apla-sia/hypoplasia of the cerebellar vermiscausing ataxia, and with the inconstantsymptoms of psychomotor retardationand episodic neonatal tachypnea/dys-pnea (Figure 9).80,81,88 –90 The radio-graphic feature of Joubert syndrome onaxial magnetic resonance brain imagingis the so-called “molar tooth sign” of themidbrain-hindbrain junction.90,91 It isdue to abnormal axonal decussation(nerve tract crossing) in the corticospinaltract and the superior cerebellar pe-duncles as the basis of the motor and be-havioral abnormalities of Joubert syn-drome.25 Ocular motor apraxia typeCogan, defined as the transient inabilityof horizontal eye movements in the firstfew years of life, may also be associatedwith Joubert syndrome (JBTS). Thissymptom has been described in patientswith mutations in the NPHP182,92

(“JBTS4”) and NPHP421 genes. Threedifferent recessive genes, NPHP1,81,90,91

AHI93,94 (JBTS type 3), and NPHP6,24,35

have been found mutated in JBTS. Threeadditional loci for JBTS have been identi-fied: JBTS1 on chromosome 9q34.395 andJBTS2/CORS2 on chromosome 11p12-q13.3.96 In addition, mutations of NPHP8/RPGRIP1L can cause Joubert syndrome ifat least one mutation is not truncating.29,36

Liver FibrosisNPHP and the related disorder BBS can beassociated with periductal liver fibro-sis,83,97–99 as has been described for a pa-tient with NPHP3 mutation.22 Patients de-velop hepatomegaly and moderate portalfibrosis with mild bile duct proliferation.This pattern differs from that of classicalcongenital hepatic fibrosis, where biliarydysgenesis is prominent, and from hepaticinvolvement in autosomal recessive PKD,

Arima syndrome (cerebro-oculo-hepato-renal syndrome),100–102 and Meckel syn-drome, which appears as bile duct prolifer-ation. Bile duct involvement in these cystickidney diseases may be explained by theciliary theory because the epithelial cellslining bile ducts (cholangiocytes) possessprimary cilia.

Brain Malformations (MeckelSyndrome)Meckel syndrome (MKS) features theassociation of renal cystic dysplasiawith occipital encephalocele, polydac-tyly, and biliary digenesis (Figure 9).Two recessive genes have been identi-fied, MKS1103 and MKS3,104 and an-other gene locus, MKS2,105 has beenmapped. Recently, a Meckel-like phe-notype was described for truncatingmutations of NPHP3,59 NPHP6/CEP290,72 and NPHP8/RPGRIP1L.29,36

Within the spectrum of NPHP-associ-ated ciliopathies, MKS is the most se-vere, leading to perinatal mortality.Consequently, MKS represents the cili-opathy of the group that encompassesdefects in most organs, and involvementis most severe and of developmentalrather than degenerative nature. For in-stance, organ defects reveal cystic dyspla-sia rather than NPHP in the kidneys, mi-crophthalmia of the eyes, bile ductdysgenesis in the liver, and occipital en-cephalocele in the brain, and bones areinvolved by postaxial polydactyly.106 Thenotion that MKS is at the most pro-nounced end of the clinical spectrum issupported by the finding that the pres-ence of two truncating mutations inNPHP8/RPGRIP1L causes MKS, whereasone “mild” mutation (missense ratherthan truncating) may cause the less severephenotype of Joubert syndrome.29 In addi-tion, the presence of two truncating muta-tions in NPHP6/CEP290 may cause anMKS-like phenotype (MKS4).72

Cardiac Defects and Situs InversusIn a patient with mutation of NPHP2,we observed a ventricular septal defect asa congenital cardiac malformation.13

Thus, the role of inversin for left–rightaxis specification that had been de-scribed in mice was confirmed in hu-

mans.51,52 The patient with situs inversusalso had a cardiac ventricular septal de-fect, which may be viewed as a “hetero-taxy” (left–right orientation) phenotypecaused by the same mechanism107 thatlead to situs inversus in this patient. Weconfirmed the phenotypic combinationof cystic kidney disease, situs inversus,and cardiac septal defect on the basis ofinversin mutations is observed in hu-mans, mice, and zebrafish.13 PKD2 genemutations that cause autosomal domi-nant PKD also represent a gene that reg-ulates left–right axis determination, act-ing upstream of Nodal, Ebaf, Leftb, andPitx2.107,108

Skeletal DefectsMultiple disease variants that are associ-ated with NPHP include skeletal defects,strongly suggesting a role of primary ciliafunction in skeletal development. Theseinclude Jeune syndrome (asphyxiatingthoracic dysplasia),109 –112 Ellis van Crev-eld syndrome,113 RHYNS syndrome (ret-initis pigmentosa, hypopituitarism,NPHP, skeletal dysplasia),114 Meckel-Gruber syndrome,103,104 and Sensen-brenner syndrome (cranioectodermaldysplasia).115,116 The association ofNPHP with cone-shaped epiphyses ofthe phalanges (types 28 and 28A) isknown as Mainzer-Saldino syndromeand occurs in patients who also have ret-inal degeneration and cerebellar ataxia.84

Interestingly, mutations in the orthologof the intraflagellar transport proteinIFT80 of Ch. reinhardtii is also a cause ofJeune syndrome117 (Figure 4), which em-phasizes again the strong evolutionaryconservation of “ciliopathy genes.”

BBS and Alstrøm SyndromeBBS exhibits renal histology similar toNPHP118,119 (Figure 4). Positional clon-ing of recessive genes mutated in BBS re-veals the molecular relationship betweenNPHP and BBS may lie in coexpressionof the respective gene products in pri-mary cilia, basal bodies, or centrosomesof renal epithelial cells.30 Alstrom syn-drome exhibits some phenotypic overlapwith BBS (NPHP, retinitis pigmentosa,deafness, obesity, and diabetes withoutmental defect, polydactyly, or hypogo-



nadism).120 The single underlying reces-sive gene, ALMS1, encodes a novel pro-tein that is a molecular component of thecentrosome.121–124 This finding, togetherwith the finding that BBS proteins local-ize to centrosomes, confirms the role ofcentrosomal proteins in cystic kidneydiseases that are associated with diabetes,obesity, and retinitis pigmentosa.125,126

Obesity is also a part of the clinical spec-trum of the ciliopathies BBS and Alstromsyndrome. Interestingly, in the Bbs6knockout mouse model, obesity is asso-ciated with hyperphagia and decreasedactivity of the mice.127

THERAPEUTIC APPROACHES TONPHP

No effective prophylaxis or treatment isavailable for NPHP other than support-ive care once chronic renal failure devel-ops and dialysis and transplantation forterminal renal failure. Gattone et al.58

showed the renal cystic phenotype of pcymice, which is the equivalent of humanNPHP type 3, can be strongly mitigatedor even reversed by treatment with thevasopressin V2 receptor antagonistOPC31260. Similar results were ob-tained using a pkd2 mouse model.128

This effect is thought to be mediated by areduction in intracellular cAMP levels.24

An important future challenge will be thedevelopment of therapies that capitalizeon what we have learned about the biol-ogy of NPHP and other cystic diseases ofthe kidney.

ACKNOWLEDGMENTS

This research was supported by grants from

the National Institutes of Health to F.H.

(R01-DK69274, R01-DK68306, and R01-

DK064614). F.H. is the Frederick G.L.

Huetwell Professor, a Doris Duke Distin-

guished Clinical Scientist, and an Investigator

of the Howard Hughes Medical Institute.

DISCLOSURESNone.

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nephronophthisis: disease mechanisms of a ciliopathy

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