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Nephronophthisis: Disease Mechanisms of a

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

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

ABSTRACT (NPHP), a recessive cystic disease, is the most frequent than 300 cases of NPHP have been pub- genetic cause of end-stage in children and young adults. Positional lished in the literature.7 It has been re- cloning of nine genes (NPHP1 through 9) and functional characterization of their ported from virtually all regions of the encoded proteins (nephrocystins) have contributed to a unifying theory that defines world.14 The incidence of the disease is es- cystic kidney diseases as “.” The theory is based on the finding that all timated at nine patients per 8.3 million15 in proteins mutated in cystic kidney diseases of humans or animal models are expressed the United States or one in 50,000 live in primary cilia or of renal epithelial cells. Primary cilia are sensory births in Canada.7,16 In the North Ameri- that connect mechanosensory, visual, and other stimuli to mechanisms of can pediatric population with ESRD, epithelial polarity and cell-cycle control. Mutations in NPHP genes cause defects in pooled data indicate a prevalence of ap- signaling mechanisms that involve the noncanonical and the proximately 5% of all children with renal sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and failure.17,18 tissue maintenance. The ciliary theory explains the multiple organ involvement in Positional cloning has identified nine NPHP, which includes retinal degeneration, , liver fibrosis, situs genes causing nephronophthisis when inversus, and mental retardation. Positional cloning of dozens of unknown genes that mutated.13,19–29 These are monogenic re- cause NPHP will elucidate further signaling mechanisms involved. Nephrocystins are cessive genes, suggesting that mutations highly conserved in evolution, thereby allowing the use of animal models to develop in each single one is sufficient by itself to future therapeutic approaches. cause NPHP in a patient bearing muta- tions and indicating their gene products J Am Soc Nephrol 20: 23–35, 2009. doi: 10.1681/ASN.2008050456 are necessary for normal kidney func- tion. Positional cloning generated new insights into disease mechanisms of Nephronophthisis (NPHP) is an autoso- transplanted into patients with NPHP.9 NPHP by revealing the mechanism is re- mal recessive that NPHP is inherited in an autosomal reces- lated to the signaling pathways of pri- constitutes the most frequent genetic sive mode.4 It was first described by Smith mary cilia, centrosomes, and planar cell cause for ESRD in the first three decades and Graham in 19452 and by Fanconi et polarity.1,13,30,31 The demonstration that of life.1–4 Renal failure manifests at a me- al.,3 who introduced the term “familial ju- nephrocystin-1 and inversin/NPHP2 lo- dian age of 13 yr. Initial symptoms are rel- venile nephronophthisis.” In juvenile calize to primary cilia of renal tubular atively mild, start at approximately age 6 yr, NPHP, renal failure develops within the cells13 was among the first findings to and consist of , , sec- first three decades of life.10–12 In contrast, support a new unifying theory of renal ondary enuresis, and .5 Regular infantile NPHP, which is characterized by fluid intake at nighttime is a characteristic mutations in NPHP2/inversin, leads to re- 12,13 Published online ahead of print. Publication date feature of the patients’ history. Renal ultra- nal failure between birth and age 3 yr. available at www.jasn.org. sound reveals normal kidney size, in- In more than 10% of cases, NPHP is asso- Correspondence: Dr. Friedhelm Hildebrandt, creased echogenicity, and corticomedul- ciated with extrarenal involvement, pri- Howard Hughes Medical Institute, Departments of lary (Figure 1A).6 Renal histology marily including retinal degeneration (Se- Pediatrics and of Human Genetics, University of exhibits a characteristic triad of cortico- nior-Løken syndrome), Michigan Health System, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109- medullary cysts, tubular basement mem- aplasia (), liver fibrosis, 5646. Phone: 734-615-7895; Fax: 734-615-1386; brane disruption, and tubulointerstitial and cone-shaped epiphyses. These clinical E-mail: [email protected] 7,8 nephropathy (Figure 1B). Disease recur- features are discussed here in light of the Copyright ᮊ 2009 by the American Society of rence has never been reported in kidneys cilia/ theory of NPHP. More Nephrology

J Am Soc Nephrol 20: 23–35, 2009 ISSN : 1046-6673/2001-23 23 BRIEF REVIEW www.jasn.org cystogenesis.30 This theory states that the cystoproteins mutated32 in renal cystic disease in humans, mice, or zebrafish are expressed in primary cilia, basal bodies, or centrosomes.30,33 Basal bodies are the foundations from which cilia are assem- bled (Figure 2). After mitosis and cell di- vision are completed, basal bodies derive from the mother centriole of the centriole pair that had organized the mitotic spin- dle during cell division. As cilia are formed from the , the daughter centriole is placed on the side of the nu- Figure 1. Morphology of nephronophthisis. (A) Renal ultrasound demonstrates in- creased echogenicity, loss of corticomedullary differentiation, and the presence of cor- cleus opposite to the basal body, thus ticomedullary cysts. In contrast to PKD, kidneys are not enlarged. (B) Renal histology in specifying cell polarity. The structure NPHP shows the characteristic triad of renal tubular cysts, tubular membrane disruption, and function of primary cilia and basal and tubulointerstitial cell infiltrates with interstitial fibrosis and periglomerular fibrosis (B bodies are delineated in Figure 2. is courtesy of D. Bockenhauer, London). Primary cilia are highly conserved structures that sense a wide variety of ex- POSITIONAL CLONING REVEALS NPHP9/NEK8,38 defining NPHP types 1 tracellular cues in a wide spectrum of ep- NEPHRONOPHTHISIS AS A through 9, respectively. This collection ithelial tissues. There is a broad range of “CILIOPATHY” of genes has made diagnostic testing pos- cues that can be received by specific cili- sible (http://www.renalgenes.org). Ho- ary receptors, including photosensation, By positional cloning, we and others mozygous deletions in the NPHP1 gene , osmosensation, and identified recessive mutations in nine account for approximately 21% of all olfactory sensation. In general, the novel genes as causing NPHP: NPHP1,19,20 NPHP cases, whereas the other genes pathogenesis of ciliopathies is based on NPHP2/inversin,13 NPHP3,22 NPHP4,21,27 contribute less than 3% each (Figure 3). an inability of epithelial cells to sense or NPHP5,23 NPHP6/CEP290,24,35 NPHP7/ As determined in more than 1000 fami- process extracellular cues.34 GLIS2,28 NPHP8/RPGRIP1L,29,36,37 and lies with NPHP, the causative genes are

Figure 2. Cilia structure and . The is a Tip hair-like structure that extends from the cell surface into the extra- complex cellular space. Virtually all vertebrate cell types can produce cilia. Eb1 Cilia consist of a microtubule-based covered by a special- ized plasma membrane. The axoneme has nine peripheral microtu- Ciliary Retrograde ϩ axoneme transport bule doublets. There may be two central microtubules (9 2 versus 9 ϩ 0 axoneme). 9 ϩ 2 cilia usually have dynein arms that link the microtubule doublets and are motile, whereas most 9 ϩ 0 cilia lack Ciliary membrane dynein 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. The Anterograde transition zone at the junction of the basal body acts as a filter for transport the molecules that can pass into or out of the cilium. Nephrocystin-1 is localized at the transition zone of epithelial cells.47 During cilio- genesis, cilia elongate from the basal body by the addition of new Cell membrane axonemal subunits to the distal tip, the plus end of the microtu- IFT cargo Transition fibers bules. Axonemal and membrane components are transported in raft Dynein Pc1/Pc2 Basal complex body macromolecular particles (complex A and B) by so-called intraflagel- 129 B Kinesin-2 lar transport (IFT) along the axonemal doublet microtubules. A IFT Anterograde transport toward the tip is driven by heterotrimeric complexes Nucleus kinesin 2, which contains motor subunits Kif3a and Kif3b and a nonmotor subunit. Mutations of Kif3a cause renal cysts and cere- bellar vermis aplasia in mice.130 Retrograde transport back to the cell body occurs via the motor protein cytoplasmic dynein 1B.131 Centrosome Adapted from Bisgrove and Yost.132

24 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 23–35, 2009 www.jasn.org BRIEF REVIEW still unknown in approximately 70% of main, localizes to adherens junctions and expressed in primary cilia, basal bodies, patients, indicating that additional genes focal adhesions of renal epithelial cells, or centrosomes.13,30 The interaction and are involved in the pathogenesis of and interacts with integral components co-localization to cilia and basal bodies NPHP (Figure 3). Evidence has been of these structures, such as p130CAS.44,45 of nephrocystin-1, inversin, and ␤-tubu- generated that more than one recessive This “adherens junction/focal adhesion lin provide a functional link between the gene may be mutated in individual pa- hypothesis” of NPHP pathogenesis49,50 pathogenesis of NPHP, the pathogenesis tients with NPHP, as has been proposed was partially reconciled with the “cilia/ of PKD, primary cilia function, and left– for the related disorder Bardet-Biedl syn- centrosome” hypothesis in an integrative right axis determination.13 Okada et al.55 drome (BBS).39 In this situation, muta- hypothesis by showing that nephrocys- previously demonstrated that inversin is tions in an additional NPHP gene may tin-4 in polarized epithelial cells co-lo- needed to position cilia in cells of the modify the clinical picture of NPHP in calizes with ␤-catenin at cell–cell contact ventral node. Inversin was then shown to the direction of a more severe extrarenal sites and to primary cilia, whereas, in di- localize to different subcellular locations, involvement.40,41 Here, disease mecha- viding cells, it localizes to centrosomes46 in a cell cycle–dependent manner (Fig- nisms of NPHP are discussed in the con- (Figure 4). ure 5). Specifically, it is found at the mi- text of the discovery of each of the genes totic spindle in mitosis, at the mid-body encoding NPHP. We describe how re- NPHP2/Inversin Implicates Cilia and in cytokinesis, and in cilia at the basal sulting insights into the function of their Planar Cell Polarity in Cystogenesis body and centrosome in interphase (Fig- gene products, the nephrocystins, helped On the basis of positional cloning12 and ure 5). All of these subcellular organelles refine the cilia/centrosome theory of re- candidate gene data,51,52 we identified are involved in regulation of planar cell nal cystic diseases. mutations in human inversin (INVS)as polarity or the cell cycle (Figure 4). the cause of infantile NPHP (type 2) with A major breakthrough was also made NPHP1 Locates to Cell Contacts and without .13 The renal in the understanding of the pathogenesis and the Cilia Transition Zone cystic changes of infantile nephronoph- of renal cystic diseases when Simons et Mutations in NPHP1 were identified as thisis (NPHP type 2) combine clinical al.56 demonstrated a role for inversin/ causing juvenile nephronophthisis type features of NPHP and of polycystic kid- NPHP2 in signaling mechanisms of pla- 1.19,20 NPHP1 encodes nephrocystin-1, a ney disease (PKD).53 We demonstrated nar cell polarity necessary to maintain protein that interacts with components of that nephrocystin-1 and NPHP2/inver- normal tubular development and mor- cell–cell and cell–matrix signaling, includ- sin interact with ␤-tubulin, which con- phology, as outlined in Figure 6.31,56 As a ing p130Cas,42 focal adhesion kinase 2,43 stitutes the microtubule axoneme of pri- consequence of this model, when inver- tensin, and filamin A and B.44,45 Nephro- mary cilia, and that they localize at sin is defective (as in NPHP type 2), ca- cystin-1 is located at adherens junctions primary cilia of renal tubular cells.13 This nonical Wnt pathway will prevail and and focal adhesions of renal epithelial was one of the first findings to support a disrupt the apical-basolateral polarity of cells,44,45 which are involved in cell–cell unifying theory of renal cystogen- renal .31 Because planar cell and cell–basement membrane contacts, esis1,30,33,54 which states that cystopro- polarity signaling is important for ori- respectively (Figure 4). It also interacts teins, which are mutated in renal cystic ented cell division, it seems logical that with the product of other nephronophthi- disease in humans, mice, or zebrafish, are Fisher et al.57 were able to demonstrate sis genes such as nephrocystin-2/inver- sin,13 nephrocystin-3,22 and nephrocystin- 21,46 4. More recently, it was shown that NPHP5 NPHP6 nephrocystin-1 is targeted to the transition NPHP4 3% 1% 2% NPHP7/ GLIS2 zone of motile and primary cilia by the pro- NPHP3 0.1% tein phosphofurin acidic cluster sorting 1% NPHP8/ RPGRIP1L 47 NPHP2 protein 1 (PACS-1). This is initiated by 1% 0.5% casein kinase 2–mediated phosphorylation NPHP1 NPHP9/ NEK8 of three critical serine residues within a 21% 0.1% cluster of acidic amino acids in nephrocys- tin, leading to PACS-1 binding and co-lo- calization of nephrocystin with PACS-1 at No mutation 70% the base of cilia.48 When NPHP1 was first identified,19 we proposed a pathogenic hypothesis that tied nephrocystin-1 in with defects 49,50 of cell–cell and cell–matrix signaling. Figure 3. Distribution of causative mutations in the NPHP1 through NPHP9 genes in a This was based on the finding that worldwide cohort of 1079 families with NPHP. Note that whereas mutations in NPHP1 nephrocystin-1 contains an SH3 do- account for Ͼ21% of NPHP, all other genes are in the range of Ͻ3%.

J Am Soc Nephrol 20: 23–35, 2009 Mechanisms of Nephronophthisis 25 BRIEF REVIEW www.jasn.org abnormal orientation of mitotic spindles in two different rodent models of cystic ABCNEPHROCYSTINS SIGNALING LOCALIZATION DCILIOPATHY kidney disease. PKD NPHP1 = 1

NPHP2/ Jeune NPHP3: A Doorstep to Treatment? = 2 Inversin PC1,2 Receptor By positional cloning, we identified mu- Nephronophthisis NPHP3 = 3 tations in NPHP3 as responsible for ado- 7 lescent nephronophthisis in a large Ven- Bardet-Biedl NPHP4 = 4 11,22 Cargo ezuelan kindred. We demonstrated 1–5 MKS IFT80 that mutations in the murine ortholog = 5 KIF NPHP5 Motor protein Nphp3 cause the renal cystic mouse mu- 3A Joubert

22 NPHP6/ = 6 tant pcy, which was demonstrated to be CEP290 responsive to treatment with a vasopres- NPHP7/ 58 = 7 sin receptor antagonist. Recently, it was GLIS2 shown that complete loss of Nphp3 func- Wnt Shh NPHP8/ = 8 RPGRIP1L tion results in situs inversus, congenital 2 heart defects, and embryonic lethality in NPHP9/ = 9 7 Transition zone NEK8 59 NPHP1 mice. In addition, truncating muta- PACS-1 tions of NPHP3 in humans causes a 1 BBS Basal body broad clinical spectrum of early embry- 1-12 Adherens onic patterning defects that resembles 2-4-5-6-8-9 junction Meckel syndrome. This includes situs in- PC2 1 Golgi Mitotic spindle versus, , central nervous sys- 2 Nucleus tem malformations, structural heart de- 8 2-4-5-6-8-9 BBS Centrosome 1-12 fects, preauricular fistulae, and a wide (orientation) range of congenital anomalies of the kid- 1 ney and urinary tract.59 Figure 4. Subcellular localization of nephrocystins to primary cilia, basal bodies, the mitotic spindle, focal adhesions and adherens junctions, and functional interaction with NPHP4 Is Conserved in other proteins mutated in renal “ciliopathies.” “Cystoproteins” are proteins of genes Caenorhabditis elegans mutated in cystic kidney diseases of humans, mice, or zebrafish. Depending on cell-cycle Mutations in the novel gene NPHP4 stage, cystoproteins are localized at different subcellular organelles (shown in gray or were identified by homozygosity map- brown),24,133 including primary cilia, basal bodies, endoplasmic reticulum, the mitotic ping and total genome search for link- spindle, centrosomes, adherens junctions, or focal adhesions. Arrows in the primary cilium indicate the direction of anterograde transport along the microtubule system age.21,60,61 Nephrocystin-4, like inversin, mediated by kinesin-2 and retrograde transport by cytoplasmic dynein 1b. (A) Most localizes to primary cilia, basal bodies, nephrocystins (blue) are located at cilia, the basal body, and centrosome in a cell centrosomes, and the cortical actin cy- cycle–dependent manner. NPHP1 is also at the transition zone, focal adhesions, and 46 toskeleton (Figure 4). Nephrocystin-4 adherens junctions. (B) Sensory cilia perceive and process cell external signals, and is conserved in Caenorhabditis elegans “cystoproteins” are involved in signaling mechanisms downstream of cilial signal recog- and expressed in ciliated head and tail nition. Downstream of cilia (pink), Wnt signaling (Figure 6) and hedgehog signaling neurons of the nematode.62 Upon (Figure 8) play a role in planar cell polarity, which is mediated (C) partially through knockdown, it exhibits a male mating orientation of centrosomes and the mitotic spindle poles (Figure 7). (D) Cilia-dependent phenotype, similar to the phenotype mechanisms of planar cell polarity seem to be central to the pathogenesis of the found upon knockdown of the polycys- ciliopathies, the most prominent of which are listed on the right. Wnt, Wnt signaling tin-1 and polycystin-2 orthologs.62 Lo- pathway; Shh, sonic hedgehog signaling pathway. calization of nphp-1 and nphp-4 to some of these ciliated neurons also overlaps with localization of the cystoprotein or- rons in C. elegans was observed.67,68 Reinhardtii uses two motor cilia (flagella) thologs polycystin-1 (lov-1), polycys- nphp-4 has an additional role in deter- for locomotion. Striking, nephrocystin-4 tin-2 (pkd-2) and with many orthologs of mining the life span of the worm.69 and at least six proteins mutated in BBS BBS proteins,62,63 similar to what has Evolutionary conservation of cys- are conserved in Ch. reinhardtii, where been described for lov-1 and pkd-2 mu- toproteins goes even further: Some cys- they are part of its basal body pro- tants.64 These data were refined for spe- toproteins have been conserved over teome.63,70 Defects of cystoprotein or- cific neuronal cell types,65,66 and the ne- more than 1.5 billion years of evolution thologs in Ch. reinhardtii have deficient cessity of nphp-1 and nphp-4 for from the unicellular organism Chlamy- intraflagellar transport and flagellar pro- morphologic integrity of ciliated neu- domonas reinhardtii to vertebrates. Ch. pulsion.71

26 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 23–35, 2009 www.jasn.org BRIEF REVIEW

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

NPHP5: The Senior-Løken pressed in centrosomes and the mitotic notype of NPHP type 6, including renal Syndrome Gene spindle in a cell cycle–dependent man- cysts, retinal degeneration, and cerebel- When the novel gene NPHP5 was identi- ner. Abrogation of NPHP6 function in lar defects.24 Nephrocystin-6 modulates fied as mutated in nephronophthisis type zebrafish causes planar cell polarity de- the activity of ATF4/CREB2, a transcrip- 5,23 all mutations detected were trunca- fects and recapitulates the human phe- tion factor implicated in cAMP-depen- tions of the encoded protein nephrocys- tin-5, and all patients had early-onset (Senior-Løken syn- drome). Nephrocystin-5 contains an IQ ABMECHANOSENSORY MECHANOSENSORY domain, which directly interacts with CILIUM AT REST CILIUM BENT BY URINE FLOW 23 calmodulin, and is in a complex with Lrp5/6 Lrp5/6 the retinitis pigmentosa GTPase regula- FLOW tor (RPGR), which when defective causes Wnt Wnt X-linked retinitis pigmentosa. Both Frizzled ? Frizzled Dvl nephrocystin-5 and RPGR are localized Axin Dvl ? in connecting cilia of photoreceptors and Axin in primary cilia of renal epithelial cells23 (Figure 4). That connecting cilia of pho- toreceptors are the structural equivalents Ca2+ of primary cilia of renal epithelial cells Inv Inv Axin β renders an explanation for retinal in- Dvl Dvl Dvl -catenin Apc destruction complex volvement in the retinal-renal syndrome Basal body Senior-Løken syndrome. GSK3β Proteasomal Inv Dvl Nucleus degradation β-catenin CYSTOGENESIS: DEFECTIVE C-Myc C-Myc ROK ? Rho REGULATION OF PLANAR CELL Lef/Tcf Lef/Tcf POLARITY? Figure 6. Inversin/NPHP2 mediates a switch from the canonical the noncanonical Wnt NPHP6/CEP290: Centrosomes as a signaling pathway, which plays a role in planar cell polarity maintenance.56 (A) This illustration Central Hub for Planar Cell Polarity of a renal tubular epithelial cell shows how Wnt signaling occurs primarily through ␤-catenin– Regulation dependent pathways in the absence of urine flow. Ligand binding by the frizzled receptor ␤ We identified by positional cloning re- results in inactivation of the -catenin destruction complex through the presence of dishev- ␤ cessive, truncating mutations in a novel eled (Dvl), increased -catenin levels, and upregulation of effector gene expression of the canonical Wnt signaling pathway. (B) Stimulation of the primary cilium (e.g., by urine flow) gene NPHP6/CEP290 as the cause of results in increased expression of inversin (Inv), which then reduces levels of cytoplasmic Dvl NPHP type 6 and Joubert syndrome type by increasing its proteasomal degradation. This allows reassembly and activation of the 24 5. Its gene product nephrocystin-6/ ␤-catenin destruction complex, thereby switching from the canonical to the noncanonical 24 Cep290 is part of the centrosomal pro- Wnt signaling pathway. The model is consistent with the finding that overexpression of teome.24 Like NPHP2/inversin (Figure ␤-catenin (equivalent to canonical Wnt signaling) leads to renal cysts in a mouse model.135 5) and NPHP4, NPHP6/CEP290 is ex- Adapted from Germino.31

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58 Mitotic spindle orientation dent renal formation. Interestingly, a along the longitudinal axis: 300–amino acid in-frame deletion of Directional cell division NPHP6/CEP290 causes retinal degenera- Planar tion only, without renal or cerebellar in- asymmetry volvement in the rds16 mouse model.24 This is in accordance with the recent find- ing that a hypomorphic mutation of

Nphp6/Cep290 represents the most fre- Disrupted planar orientation: quent cause of Leber’s congenital amauro- Non-directional cell division, cyst development sis.24 Mutations in NPHP6/CEP290 have been confirmed as causing Joubert syn- drome with and without renal involve- ment.35 Furthermore, truncating muta- PKD tions in NPHP6 were shown to cause Meckel-Gruber syndrome.72 Correct orientation of the mitotic spin- Figure 7. Defects of cystoproteins lead to disruption of planar cell polarity and thereby to dle and centrosomes with respect to the renal cysts through to malorientation of the centrosome or mitotic spindle complex. Correct longitudinal axis of the tubule is critical for orientation of the mitotic spindle and centrosomes with respect to the longitudinal axis of the proper apical-basolateral polarity (Figure tubule is critical for proper planar cell polarity (i.e., the orientation of an epithelial cell layer in 7). Noncanonical Wnt signaling (see Fig- three-dimensional space). Noncanonical Wnt signaling (see Figure 6) is involved in regulation ure 6) is involved in these processes during of planar cell polarity during renal tubular morphogenesis; in rodents 2 wk post partum, the renal tubular morphogenesis, when in ro- tubules still elongate. The structure that would result from disruption of this longitudinal dent renal tubules still elongate postnatally. orientation is a dilated tubule or cyst. Adapted from Germino.31 The structure that would result from dis- ruption of the longitudinal growth would be a dilated tubule or cyst. Recently, evi- Cilium Cilium dence for a role of planar cell polarity in Promote Smo Gli3 57 Hedgehog renal cystic diseases was advanced by Plasma processing PKA PKA membrane measuring orientation of the mitotic spin- Ptch1 Ptch1 Gli1 Gli2 Gli3 Gli1 Gli2 Gli3 dle through three-dimensional imaging of Smo renal tubules. Comparison of the distribu- Cos2 ? Cos2 tion of the mitotic angles in wild-type ani- Sufu GliAct Gli3R Sufu GliAct Gli3R Intracellular mals and rodent cystic kidney disease vesicle Iguana Iguana models suggest that mitotic angles of two rodent models of cystic kidneys, the Figure 8. The hedgehog signaling pathway may be involved in renal cystogenesis. In HNF1␤-deficient mouse model and the the hedgehog pathway of vertebrates, upon binding of the Shh ligand to the patched pck rat model, were clearly different from (Ptch1) receptor, repression of the smoothened (Smo) receptor to be inserted into the wild-type littermates.57 cilium membrane is relieved, and posttranslational modification of the Gli transcription factors within the cilium induces both their activator (GliAct) and repressor (GliR) functions. Several studies in mice have demonstrated that ciliary proteins are needed for hedgehog NPHP7/GLIS2: The Link to signaling. Recently, the related transcription factor Gli-similar 2 (GLIS2) was found to be Hedgehog Signaling mutated in NPHP type 7. Adapted from Huangfu and Anderson.136 Recently, we identified mutations in the gene NPHP7/GLIS2 in a Cree Indian kin- dred encoding the transcription factor tal tubular segments of the kidney, which hedgehog is the maintenance of stem cell Gli-similar protein 2 as the cause of might provide an explanation for why pools in postembryonic tissues. NPHP type 728 (Figure 4). Starting at 8 PKD kidneys are enlarged with hyper- wk of age, Glis2 mutant mice show severe proliferation prevailing, whereas in NPHP8: A Clinical Spectrum from renal atrophy and fibrosis resembling NPHP, kidney size is reduced. GLIS2 is Meckel Syndrome to Joubert human nephronophthisis.28 Differential related to the GLI transcription factor, Syndrome gene expression studies on Glis2 mutant and these findings implicate the hedge- Recently, missense and truncating muta- kidneys demonstrated that genes pro- hog pathway in the pathogenesis of cystic tions in the RPGRIP1L gene were identified moting epithelial-to-mesenchymal tran- kidney diseases (Figure 8). It is a signal- by positional cloning as the cause of a Jou- sition and fibrosis are upregulated in the ing pathway that controls cell determina- bert syndrome-like phenotype (cerebro- absence of Glis2.28 Striking, there was tion and tissue patterning during embry- oculo-renal syndrome [CORS]) and also prominent apoptosis present in dis- ogenesis. The other known role of Meckel syndrome (Figure 4).29,36 It was

28 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 23–35, 2009 www.jasn.org BRIEF REVIEW shown that defects in the mouse ortholog Rpgrip1l (Ftm) recapitulate the cerebral, renal, and hepatic defects of CORS and Meckel syndrome. RPGRIP1L co-localizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4.29 RPGRIP1L missense mutations found in individuals with CORS diminish the interaction between RPGRIP1L and nephrocystin-4. Missense mutations were seen 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, Joubert syndrome/CORS, and nephronophthisis on the basis of distinct mutations of iden- tical genes (multiple allelism).

NPHP9: The Link From Cilia to Cell- Cycle Control We recently identified three different Figure 9. Ciliopathies feature a broad spectrum of organ involvement, shown here highly conserved amino acid changes in for the nephronophthisis-related ciliopathies. There is overlap between different the gene NEK8 (never in mitosis kinase 8) syndromes: Exclusive kidney involvement is called nephronophthisis. Associated 73 as causing NPHP type 9. One of the mu- retinal degeneration in known as Senior-Løken syndrome. Involvement of the cere- tations identified is positioned in the same bellum represents Joubert syndrome. In the most severe form, Meckel syndrome, RCC1 domain in which a missense muta- brain malformations, liver fibrosis, heart defects, polydactyly, and perinatal mortality tion causes renal cystic disease in jck are associated. It has recently become evident that the spectrum can vary by at least mice.74,75 Upon expression in medullary two mechanisms: First, multiple allelism, in which a hypomorphic mutation may cause collecting duct cells, all three mutant forms a milder phenotype. For example, a splice site mutation of NPHP6 may cause Leber of NEK8 showed defects in ciliary and cen- congenital optical atrophy (LCA) only. In another example, the presence of one trosomal localization to varying degrees, nontruncating mutation in NPHP8 can rescue the phenotype from Meckel syndrome supporting the notion that mutations in to Joubert syndrome. Second, NPHP genes can modify each other. For instance, NPHP6 and AHI1 modify recessive NPHP1 mutations to express a more severe NEK8 cause NPHP type 938 (Figure 4). As phenotype.137 NEK8 plays a major role in cell-cycle regu- lation, these findings provide a direct link between a protein defective in renal cystic THE CILIARY THEORY EXPLAINS tricular septal defect.13 In some in- disease and the role of centrosomes for cell- EXTRARENAL INVOLVEMENT OF stances, there seems to be a genotype/ cycle regulation (Figure 4). In this context EYE, BRAIN, AND LIVER IN NPHP phenotype correlation regarding it is interesting that also for polycystin-1 pleiotropy. For instance, there is in- and -2 signaling, the renal cystic phenotype A prominent feature of NPHP is in- volvement of the in all known has been linked to cell growth regulation. volvement of multiple organs (pleiot- cases with mutations of NPHP5 or Polycystin-1 expression activates the JAK- ropy) outside the kidney. Defects in NPHP6. In other instances, such as STAT pathway, thereby upregulating other organs are usually of a degenera- NPHP1 mutations, the molecular basis p21(waf1) and inducing cell-cycle arrest in tive or developmental nature (Figure of eye involvement is unknown. The G0/G1.76 Cell-cycle arrest required poly- 9). Specifically, NPHP may be associ- pleiotropy of NPHP has now found a cystin-2. Involvement of polycystin-1 and ated with tapetoretinal degeneration potential explanation in the ciliary hy- -2 signaling in the JAK/STAT pathway (Senior-Løken syndrome78,79), cere- pothesis of cystic kidney diseases (Fig- might explain how mutations of either bellar vermis aplasia (Joubert syn- ure 9). The extrarenal organ involve- gene can result in dysregulated growth.76 drome80,81), ocular motor type ment in NPHP is discussed by organ Involvement of cell-cycle regulation in re- Cogan,82 mental retardation,24 liver fi- system as follows (Figure 9). nal cystic disease was confirmed by dem- brosis,83 or cone-shaped epiphyses of onstration that two mouse models of PKD the phalanges (Mainzer-Saldino syn- Retinal Involvement (Senior-Løken (jck and cpk) can be efficiently treated with drome84). Infantile NPHP type 213 can Syndrome) the cyclin-dependent kinase inhibitor be associated with situs inversus,13 reti- The renal-retinal involvement in Senior- roscovitine.77 nitis pigmentosa,85 or cardiac ven- Løken syndrome can be explained by the

J Am Soc Nephrol 20: 23–35, 2009 Mechanisms of Nephronophthisis 29 BRIEF REVIEW www.jasn.org fact that the primary cilium of renal epi- Arima syndrome (cerebro-oculo-hepato- mans.51,52 The patient with situs inversus thelial cells is a structural equivalent of renal syndrome),100–102 and Meckel syn- also had a cardiac ventricular septal de- the connecting cilium of photoreceptor drome, which appears as bile duct prolifer- fect, which may be viewed as a “hetero- cells in the retina.86 We have shown that ation. Bile duct involvement in these cystic taxy” (left–right orientation) phenotype nephrocystin-5 and nephrocystin-6 are kidney diseases may be explained by the caused by the same mechanism107 that expressed in the connecting cilia of pho- ciliary theory because the epithelial cells lead to situs inversus in this patient. We toreceptors.72,87 lining bile ducts (cholangiocytes) possess confirmed the phenotypic combination primary cilia. of cystic kidney disease, situs inversus, Cerebellar Vermis Aplasia (Joubert and cardiac septal defect on the basis of Syndrome) Brain Malformations (Meckel inversin mutations is observed in hu- In Joubert syndrome, NPHP is associ- Syndrome) mans, mice, and zebrafish.13 PKD2 gene ated with coloboma of the eye, with apla- Meckel syndrome (MKS) features the mutations that cause autosomal domi- sia/hypoplasia of the cerebellar vermis association of renal cystic dysplasia nant PKD also represent a gene that reg- causing ataxia, and with the inconstant with occipital , polydac- ulates left–right axis determination, act- symptoms of psychomotor retardation tyly, and biliary digenesis (Figure 9). ing upstream of Nodal, Ebaf, Leftb, and and episodic neonatal tachypnea/dys- Two recessive genes have been identi- Pitx2.107,108 pnea (Figure 9).80,81,88–90 The radio- fied, MKS1103 and MKS3,104 and an- graphic feature of Joubert syndrome on other gene locus, MKS2,105 has been Skeletal Defects axial magnetic resonance brain imaging mapped. Recently, a Meckel-like phe- Multiple disease variants that are associ- is the so-called “molar tooth sign” of the notype was described for truncating ated with NPHP include skeletal defects, midbrain-hindbrain junction.90,91 It is mutations of NPHP3,59 NPHP6/ strongly suggesting a role of primary cilia due to abnormal axonal decussation CEP290,72 and NPHP8/RPGRIP1L.29,36 function in skeletal development. These (nerve tract crossing) in the corticospinal Within the spectrum of NPHP-associ- include Jeune syndrome (asphyxiating tract and the superior cerebellar pe- ated ciliopathies, MKS is the most se- thoracic dysplasia),109–112 Ellis van Crev- duncles as the basis of the motor and be- vere, leading to perinatal mortality. eld syndrome,113 RHYNS syndrome (ret- havioral abnormalities of Joubert syn- Consequently, MKS represents the cili- initis pigmentosa, hypopituitarism, drome.25 Ocular motor apraxia type opathy of the group that encompasses NPHP, skeletal dysplasia),114 Meckel- Cogan, defined as the transient inability defects in most organs, and involvement Gruber syndrome,103,104 and Sensen- of horizontal eye movements in the first is most severe and of developmental brenner syndrome (cranioectodermal few years of life, may also be associated rather than degenerative nature. For in- dysplasia).115,116 The association of with Joubert syndrome (JBTS). This stance, organ defects reveal cystic dyspla- NPHP with cone-shaped epiphyses of symptom has been described in patients sia rather than NPHP in the kidneys, mi- the phalanges (types 28 and 28A) is with mutations in the NPHP182,92 crophthalmia of the eyes, bile duct known as Mainzer-Saldino syndrome (“JBTS4”) and NPHP421 genes. Three dysgenesis in the liver, and occipital en- and occurs in patients who also have ret- different recessive genes, NPHP1,81,90,91 cephalocele in the brain, and bones are inal degeneration and cerebellar ataxia.84 AHI93,94 (JBTS type 3), and NPHP6,24,35 involved by postaxial polydactyly.106 The Interestingly, mutations in the ortholog have been found mutated in JBTS. Three notion that MKS is at the most pro- of the intraflagellar transport protein additional loci for JBTS have been identi- nounced end of the clinical spectrum is IFT80 of Ch. reinhardtii is also a cause of fied: JBTS1 on chromosome 9q34.395 and supported by the finding that the pres- Jeune syndrome117 (Figure 4), which em- JBTS2/CORS2 on chromosome 11p12- ence of two truncating mutations in phasizes again the strong evolutionary q13.3.96 In addition, mutations of NPHP8/ NPHP8/RPGRIP1L causes MKS, whereas conservation of “ciliopathy genes.” RPGRIP1L can cause Joubert syndrome if one “mild” mutation (missense rather at least one mutation is not truncating.29,36 than truncating) may cause the less severe BBS and Alstrøm Syndrome phenotype of Joubert syndrome.29 In addi- BBS exhibits renal histology similar to Liver Fibrosis tion, the presence of two truncating muta- NPHP118,119 (Figure 4). Positional clon- NPHP and the related disorder BBS can be tions in NPHP6/CEP290 may cause an ing of recessive genes mutated in BBS re- associated with periductal liver fibro- MKS-like phenotype (MKS4).72 veals the molecular relationship between sis,83,97–99 as has been described for a pa- NPHP and BBS may lie in coexpression tient with NPHP3 mutation.22 Patients de- Cardiac Defects and Situs Inversus of the respective gene products in pri- velop hepatomegaly and moderate portal In a patient with mutation of NPHP2, mary cilia, basal bodies, or centrosomes fibrosis with mild bile duct proliferation. we observed a ventricular septal defect as of renal epithelial cells.30 Alstrom syn- This pattern differs from that of classical a congenital cardiac malformation.13 drome exhibits some phenotypic overlap congenital hepatic fibrosis, where biliary Thus, the role of inversin for left–right with BBS (NPHP, retinitis pigmentosa, dysgenesis is prominent, and from hepatic axis specification that had been de- deafness, , and without involvement in autosomal recessive PKD, scribed in mice was confirmed in hu- mental defect, polydactyly, or hypogo-

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