Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. Ghaffarieh Ning Ke Senior-Løken Syndrome NPHP1-related In distribution INPP5E Defective hitne,20;Vln,Aa,Pdre,Ydr hitne,20) eet nclarsl naclass a in result cilia & in al- Satir Defects of 2009; 2009). Yoder, surface & Christensen, the Haycraft, & O’Connor, from Yoder, Berbari, Pedersen, extending 2008; Awan, structure al., Veland, et microtubule-based 2007; (Anderson immotile types Christensen, solitary, cell mammalian a all is most cilium primary cells. The tubular renal of NPHP1 membrane of ciliary role the novel in a spe- phosphoinositide Words: suggests INPP5E ciliary morphology, Key of regulating cilia expression in disorganized decreased involved with The is coupled control. it cilium, healthy that primary a 5-phosphatases to the phosphoinositide com- for compared in critical sections staining cystic as cifically kidney recognized of disorganized of recently loss immunostaining showed been showed and have (INPP5E) membrane kidney Phosphoinositides ciliary tubules. trans- resected the renal renal of the in 9-year-old a ponents cilia and of a of nephrectomy loss microscopy report bilateral with we electron undergone structures con- had Here and electroretinogram patient cilia. decreased Immunohistochemistry The a primary degeneration. plant. with retinal of presents early who (TZ) juvenile with deletion, zone sistent of NPHP1 gene. transition with cause (NPHP1) patient dege- the frequent 1 syndrome retinal most at Senior-Løken type and The functions nephronophthisis blindness. nephronophthisis which the progressive with nephrocystin-1, in and presents mutation disease which is renal disorder nephronophthisis end-stage genetic to rare leading a neration, is syndrome Senior-Løken ABSTRACT membrane ciliary the in phosphoinositide ciliary the regulating disorganized in of with involved cells. coupled is components tubular it cilium, that primary renal critical NPHP1 the of of in as role specifically staining cystic novel recognized INPP5E of a of disorganized recently loss suggests expression morphology, showed showed decreased been cilia (INPP5E) The 5-phosphatases have kidney control. phosphoinositide healthy Phosphoinositides resected for a to sections tubules. the nephrectomycompared kidney renal with of bilateral of immunostaining in presents undergone and microscopy who cilia membrane had electron ciliary deletion, of patient and NPHP1 loss The with zone Immunohistochemistry with degeneration. patient transition transplant. structures the retinal syndrome the renal in Senior-Løken early at a mutation 9-year-old with functions a and is consistent which report nephronophthisis electroretinogram nephrocystin-1, we juvenile protein to decreased Here of the leading a cilia. cause degeneration, encodes primary frequent retinal NPHP1 of most and gene. (TZ) nephronophthisis The (NPHP1) with 1 blindness. presents type progressive which nephronophthisis and disorder disease genetic renal rare end-stage a is syndrome Senior-Løken Abstract 2020 23, August 3 2 1 nin nvriyPru nvriya Indianapolis at University Purdue Medicine University of Indiana Department School Medical Medicine Harvard of School University Stanford 1 mleSong Emilie , 2 og Alvarado Jorge , rmr ii,NH1 eirLknsnrm,nprnptii,tasto oe INPP5E zone, transition nephronophthisis, syndrome, Senior-Løken NPHP1, cilia, Primary 1 rn Sendayen Brent , 1 ioWang Biao , 1 1 hlp Prosseda Philipp , ioa Berbari Nicolas , 1 3 1 agHu Yang , u-h Chang Kun-Che , NPHP1 1 n agSun Yang and , noe h protein the encodes 1 Alireza , 1 Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. irsoy lcrnmcocp eelda reua B atr,cnitn rqetyo w rthree or two of of frequently mutation electron consisting transmission of by pattern, profiles impact TBM TBM the irregular and thickened cells, determine an a epithelia revealed to renal highlighted microscopy of order magnification TBM Electron cortical and In Higher microscopy. cilia Enlarged (TBM). primary human region. membrane junction. on corticomedullary corticomedullary basement NPHP1 the the tubular ( at in multilayered kidney tubules present and human atrophic was healthy and formation a tortuous cyst of of kidney predominance analysis his a identical of with analysis an histopathological alongside patient, performed this Knoers, 1D of was & phenotype nephrectomy Lilien, renal by Stokman, mem- the 2014; basement obtained determine Sayer, To tubular & cysts, 2015). (Srivastava Wolf, corticomedullary nephropathy 1993; of tubulointerstitial responses triad and characteristic rod disruption a diminished display brane patients demonstrated NPHP1 deletion of NPHP1 Kidneys with function. patient cone 50 the impaired was summary, overall ERG In and light-adapted the shown). of not value (data b The 143 control. and age-matched patient The the delay. to time compared implicit reduced without scotopic) 217 10.0 36 ( with and was eyes 3.0 (0.01) 120 and both ERG (0.01, was scotopic in dark-adapted (3.0) response The response the rod adaptation. of cone the value dark and for an b of provides rod reduced minutes which was decreased 30 ERG, b-wave a field after the showed Full recorded ERG loss. was field flash function, visual photopic ( retinal bilateral overall periphery despite of or normal of photographs macula typically assessment fundus the are Color patients in normal. NPHP1 scars also in On or eyes. was lesions eyes changes, both bilateral pigmentary in both underwent 1A without 20/20 the unremarkable, he was of were presented acuity which segment eyes patient visual for anterior both The his the disease, showed degeneration. examination, kidney renal exam retinal presented lamp Ophthalmic cystic end-stage of initially transplant. slit to with signs renal child progressed consistent early a The then were and and patient. nephrectomy failure polydipsia, findings male renal and ultrasound develope 9-year-old polyuria Subsequent to a with 2. on 2014). of age went R, phenotype at He 2013; al., clinical disease. failure et the renal (Aggarwal manifestations progressive report (OMA) ophthalmologic dys- apraxia with we reported retinal ocular-motor study, frequently of and this most degeneration degrees The In retinal different 2013). been includes have al., and NPHP et variable of (Aggarwal is al., areas cataracts et syndrome in and (Hildebrandt Senior-Løken found trophy adhesions in been involvement focal also ocular and has junctions The NPHP1 2017; adherens 2012). Reiter, junctions, 2010). al., tight & Omran, et primary including Garcia-Gonzalo Zhou of 2017; contact, 2006; TZ 2009; Pelletier, cell al., the other & and to et Goncalves to body cell (Fliegauf basal of Similar 2020; photoreceptors the retinal 2015). al., at Wolf, and localize et cells to 2009; Gogendeau found tubular al., been renal et has in is protein (Hildebrandt cilia treatment NPHP1 date the no to product, Currently, patients gene 2012). NPHP nephrophthisis al., in the et in madaro- reported Ronquillo Deletion and mality 2013; pathogenesis. metacarpals) Gupta, disease (short prevent & hand to Kaverappa, available small may Yadav, syndrome anomalies, Jain, Senior-Løken cerebellar (Aggarwal, of and manifestations sis dermatological clinical defects, skeletal, kidney include and also degeneration retinal Bernstein, to (Ronquillo, develop- addition eyes with In of and associated Deletion kidneys is the 1993). (TZ), affects Knoers, 2012). zone mainly & Baehr, transition which NPHP, Lilien, & ciliary and Stokman, the and syndrome 2014; at Senior-Løken polyuria Sayer, residing of disease & by ment protein Srivastava kidney ciliary clinic 2011; end-stage important the of Ali, an cause & in NPHP1, genetic (Ahmed characterized frequent 30 most ciliopathy Nephronoph- the age renal constitutes 2009). abnormalities before NPHP cystic Otto, cerebral manifestations. recessive & core and autosomal Attanasio, as anemia disease Hildebrandt, an 2013; renal is al., degeneration, (NPHP) et thisis retinal (Halbritter include ciliopathies usually called collectively that diseases multi-organ of .Vsa edeaiainsoe ofcldfcsi ohee ( eyes both in defects focal no showed examination field Visual ). .HEsann fteptetskde etossoe iueslrsn uuonesiilprocess tubulointerstitial sclerosing diffuse a showed sections kidney patient’s the of staining H&E ). μ ntecnrlptet h mltd fbt n -aeo h oersos a bilaterally was response cone the of b-wave and a both of amplitude The patient. control the in V μ Dcmae ih212 with compared OD V μ ntecnrlptet ormral hne eefudi 0H ikri ihreye either in flicker 30-Hz in found were changes remarkable No patient. control the in V μ ntecnrlptet R 1.)ws152 was (10.0) ERG patient. control the in V μ Dcmae ih140 with compared OD V 2 NPHP1 eerpeet h edn eei abnor- genetic leading the represents gene i 1B Fig μ ntecnrlptet ERG patient. control the in V i 1C Fig .Clrfnu photographs fundus Color ). .Teapiueof amplitude The ). μ Dcompared OD V μ Di the in OD V Fig. Fig Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. PPpoen r motn euaoso iir nrneadei o ies ra fcomponents a of as array recognized diverse been a have for recently exit which phosphoinositides, and cells. of entrance epithelial regulation ciliary renal human the of of Therefore, regulators cilia 2010). primary important (Omran, in are localization NPHP4 proteins 4.2 the controlling NPHP only in in to role also a compared but plays NPHP4, cilia it of the that enrichment ( of group abnormal base patient control an the the the from demonstrated at sections group only renal deletion in not contrast, NPHP1 increased In ( ( significantly cilia. NPHP8 axoneme was the alteration of ciliary NPHP4 of no independently base deletion, revealed the function images NPHP1 at its confocal with only exerts for of localized controls NPHP1 Analysis NPHP4 healthy that control, Arl13b. and healthy indicating marker deletion ciliary localization, NPHP1 the NPHP8 with and patient in NPHP8 the or from sections NPHP4 renal either co-stained localization we NPHP4 hypothesis, affect this cells directly tubular would shown renal NPHP1 been of NPHP8 have of cilia and NPHP8 the NPHP1 and of NPHP4 both Furthermore, base binds 2011), the other. directly each to that to localize bridge bind to a directly demonstrated as cannot have NPHP8 acts studies and NPHP4 Previous NPHP1 2011): 2011). al., al., et et (Sang TZ (Williams and AC3 cilia Two LAP-tagging MKS-complex- cells, In TZ-deficient in by mammalian in located 2010). axoneme. 2011). In abnormal aberrantly are al., and Omran, are proteins) complex. homologues et ciliary body 2017; MKS both (Garcia-Gonzalo and are basal Pelletier, cilia PKD2 complex and the & deficient NPHP III diffusion (Goncalves between cyclase the membrane (adenylyl exit cilium, selective PKD2 identified: a and and the been as have entry functions of complexes TZ protein region protein that ciliary shown proximal kidney. have regulating human the systems in model barrier, of function diverse compartment and in Our maintenance studies a cilia Numerous 2019). is normal al., type function.(Williams, et for TZ cell (Lewis gene required be phenotypes The in be may specific may function having differences members TZ NPHP1 species TZ that that to some demonstrate suggest in to due findings mutations begun be (Delous with also cilia specific, might have patient-derived tissue data phenotype for and Recent data in 2010). our decreases difference Yoder, with significantly & This consistent Masyukova, knockout is which 2009). NPHP1 cells, However, al., MDCK et in 2008). length al., ciliary and et ciliation (Jiang nephronophthisis of characteristics 5.6 ( from patient reduced was length ciliary that revealed ( 78.5 cilia cells from tubular renal cells renal ciliated human patient of 60 NPHP1 were proportion to the marker, cilia, patient reduced IFT primary significantly normal NPHP1 kidney specific of control loss cilia showed We ( with a frequency shortened Compared 88 nephronophthisis. and Transport with disorganized cilia. Intraflagellar were patient primary and acetylated a assess marker markers, of to membrane ciliary 2006) those employed biopsy Typical cilia to al., kidney. kidney a findings healthy et Arl13b the a a compared has marker, in (Fliegauf from and deletion et samples microscopy cilia knowledge NPHP1 control immunofluorescence Shi primary relevant our with confocal 2011; in patient To assess with human al., biopsy we a renal et 2011). Here, in the Sang examined cilia al., a 2006; primary done. et has renal al., been Williams of body, et signaling not content basal 2012; Fliegauf cilia and the 2014; the Johnson, morphology frequency, of enter al., & cilia proteins distal et tubular Szymanska what just (Awata renal regulating 2017; sub-compartment systems of in cilia al., model TZ implicated a diverse been ciliary TZ, in also the The has compartment to and cells. localize content membrane cultured proteins renal unique indicating and nephrocystin cells, mice that epithelial in demonstrated tubular epithelia previously the been of shown side has As apical It the flattened. was on cysts seen tubular were the cilia dysfunction. of primary cilia lining fewer the 1D, while Figure excessively in folded were which layers membrane vdneta hypa la oewti ii.Bsdo hs tde,w yohszdta loss that hypothesized we studies, these on Based cilia. within role clear a play they that evidence i.2F Fig. i.2C Fig. .Peiu tde aesonta iewt PP eeind o eeo pathological develop not do deletion NPHP1 with mice that shown have studies Previous ). i.2G Fig. ± nvitro in .%i h PP eeinptet niaigta PP nune iignssin ciliogenesis influences NPHP1 that indicating patient, deletion NPHP1 the in 7.3% i.2E Fig. .Qatttv nlsssoe ht97.78 that showed analysis Quantitative ). .Teerslssgetta h PP-PP neato scnevdand conserved is interaction NPHP1-NPHP4 the that suggest results These ). idn,ta PP,NH4adNH8hv togmta interaction mutual strong a have NPHP8 and NPHP4 NPHP1, that binding, i.2A Fig. .I diin unicto fimnfloecnl aee rmr cilia primary labeled immunofluorescently of quantification addition, In ). .Qatfiaino ii hc r akdb r1bantibody Arl13b by marked are which cilia of Quantification ). ± C.elegans 1.2 nvivo in 3 μ ntehatyptett 3.2 to patient healthy the in m nvivo in RMpoenadmmrn-soitdRP2 membrane-associated and protein TRAM , u rdc oatrto fNH8 otest To NPHP8. of alteration no produce but , and nvitro in ± .5 ea pteilclsi the in cells epithelial renal 3.85% Dlu ta. 09 Sa 2009; al., et (Delous ± α- 1.0 uui naxoneme an tubulin μ nvitro in nteNPHP1 the in m ± i 2B Fig 23 nthe in 12.3% ± whereas , ge al., et ng .%in 7.2% .In ). Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. PP eein inyseie ssona o lf)adhg rgt anfiain inyhistology Kidney membrane basement magnification. tubular (right) cysts, high corticomedullary and of and (left) triad with low hematoxylin characteristic patient at Representative the the shown illustrates and (D) patient is human ERG. NPHP1 normal and specimen 3.0 of in with time Kidney pattern photopic points implicit histological demonstrating paracentral in increased deletion. the of showing and examination showing NPHP1 cluster OD sections ERG, field kidney a of 0.01 (H&E)-stained Vision ERG as scotopic eosin standard present (B) in field plots dystrophy. Full grayscale amplitude fundus retinal (C) The reduced scotoma. normal patient. or and showing this pallor sensitivity deletion in decreased disc loss NPHP1 deletion. field optic with NPHP1 visual patient without bilateral with the eyes patient of both a photographs in in fundus cyst color kidney Representative to and (A) ability degeneration its retinal Early and forming 1. in transition Fig. NPHP1 INPP5E of regulates input turn the legends in focus Figure which into a normally, bring as We functions acts stability. TZ. NPHP4 NPHP1 for cilia the that gate which influence in ciliary suggests in a present which sample TZ as NPHP4 NPHP4, the act a of the may in expression for NPHP1 altered abnormal that scaffold impaired is an hypothesis structural INPP5E likely our detected of which confirming we localization abnormalities show Furthermore, deletion, We ciliary NPHP1 whichlipids. morphological degeneration. the with syndrome, exhibit retinal that patient Senior-Løken and biopsy show the failure of also from renal renal case we patient’s had Importantly, diagnosed patient the function. a The in normal protein. report phosphoi- TZ cilia we key the study, primary a of present that of amount the such deletion the In proteins, a regulating from lipids. TZ derives in on for role depend gate a Supporting to ciliary of have play 2017). shown a cilia studies Pelletier, to been within & recent has reported (Goncalves PIP2 More cilia been lipids nositide vertebrate 2018). has for within Dutcher, gate RPGRIP1L/MKS5 INPP5E ciliary & TCTN1. governing of specific as Guo, in location a involved (Lin, as the not act cilia notion, is could NPHP1 this vertebrate TZ that in the suggesting proteins that cells, vertebrate proposed these studies in of previous Sstr3 Although transition or clear. the Arl13b in not bio- of gate still of levels ciliary are field ciliary a gating active as alter ciliary acts gatekeeper, an regulate NPHP1 ciliary is they that the TZ which shown as have of by serve mechanisms proteins function exact TZ the that the ciliopathies, demonstrated but severe have many publications signaling Numerous with relevant research. associated medical the are elucidating defects targets. and its therapeutic by TZ novel Because mechanism vertebrate developing the the toward Revealing at disorder. steps INPP5E biological important of same represent amount pathways the and the of of mild regulates expression manifestation the abnormal NPHP1 clinical represent in which nephronophthisis the results and of deletion syndrome versions NPHP1 Joubert severe that that the hypothesis shows the study & supports Our Schurmans, which Floyd, 2009). that INPP5E, Long, al., showed syndrome(Constable, et publications Joubert Jacoby for Previous 2020; responsible Caspary, degeneration. clinical are overlapping retinal mutations with INPP5E and and ciliopathies disease NPHP1 of kidney types cystic two including are manifestations, syndrome Joubert and nephronophthisis Interestingly, it ( tissue, regulation. normal tissue ( in healthy patient cilia to deletion primary compared deletion NPHP1 of NPHP1 the axoneme with of the patient 42.40 cilia along a to expressed the both from was from assessed tissue INPP5E we absent renal described INPP5E, While was of against control. previously cilia antibody healthy the primary monoclonal a on the phosphoinositide a and controlling within Using Based for INPP5E cells. 2009). critical epithelial of al., renal distribution be human may the et (INPP5E), of Joubert NPHP1 Jacoby cilia in the that 5-phosphatase instability the 2017; hypothesized in ciliary into we inositol al., entry for cilia, residing et responsible of in is complexes Dyson NPHP1 mutation cilium, of 2015; primary these distribution a the al., by of that et axoneme influenced (Chavez the shown in syndrome be have localize to also groups found could is Several which membrane, zone. ciliary transition the ciliary of component critical ± 38%o ea pteilclsi h PP eeinptethdanra NPEexpression, INPP5E abnormal had patient deletion NPHP1 the in cells epithelial renal of 13.83% i.2H Fig. .elegans C. .Ti aaidctsaciia oefrNH1i phosphoinositide in NPHP1 for role critical a indicates data This ). u itei nw bu h osbeivleeto PP as NPHP1 of involvement possible the about known is little but , .elegans C. 4 i.2D Fig. Wlim ta. 01,NH1dfiinyddnot did deficiency NPHP1 2011), al., et (Williams .Qatttv nlsssoe htup that showed analysis Quantitative ). Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. yo,J . odi,S . eny .J,Hkm . ioms,T,Flhr .J,...Mthl,C A. C. Mitchell, . . Saunier, . J., . A. Fulcher, function. T., . zone DiTommaso, transition S., . cilia doi:10.1083/jcb.201511055 Hakim, J., phosphoinositide-dependent R., 247-263. S. regulates Feeney, Salomon, INPP5E E., with A., S. (2017). associate Conduit, Bivic, and M., Le morphogenesis J. epithelial F., Dyson, for Silbermann, required M., are H. nephrocystin-4 Par6. and and PALS1/PATJ Gaude, Nephrocystin-1 E., phosphatidyli- (2009). N. ciliary S. signaling. Hellman, The Shh M., (2020). in Delous, T. roles Caspary, regulatory & negative S., and Schurmans, doi:10.1242/dev.183301 positive A., (3). plays K. Inpp5e Floyd, phosphatase B., nositol A. (2015). Long, N. S., S. Constable, Schiffmann, & Output. S., complex Signaling Schurmans, Hedgehog 34 a Sonic A., as Cell, and d’Exaerde, Trafficking cilium Kerchove Dev Regulates Content primary de Phosphoinositide The J., Ciliary of Sande, (2009). Van Modulation B. K. S., G. B. Ena, Yoder, Witman, M., & Chavez, . J., C. . Haycraft, K., center. . transition A. signaling J., the O’Connor, at F., G. proteins N. Pazour, soluble Berbari, D., large and K. proteins Bellve, membrane F., of trafficking K. zone. ciliary Lechtreck, controls Primary C., NPHP4 Standley, (2008). T. (2014). S., Stearns, Takada, & R., J., C. Awata, skeleton. Jacobs, A., the J. for Helms, rare sensors A., S. with cellular Brugmann, syndrome B., cilia: Senior-loken A. Castillo, (2013). T., A. C. Gupta, Anderson, & V., report. Kaverappa, case S., author. a Yadav, D., corresponding manifestations: Jain, the K., from H. request Aggarwal, restrictions. on ethical available or privacy are to study due References available this publicly of not findings are the data support The that data The manuscript. Statement the Availability improving Data for Kowal Tia Dr. thank We Acknowledgments: (n=50). expression abnormal 10 p with (A-C) test, cells Student’s immunomicroscopy bars: using of Confocal performed Scale Quantification was (H) patient. E-H phosphoinositide INPP5E. deletion in of for NPHP1 analysis deletion expression Statistical stained the NPHP1 Aberrant sections from (D) kidney cells the Quan- patient tubular from (n=50). (G) of renal cells NPHP4 of NPHP4. of tubular of cilia and expression renal in NPHP8 cells abnormal 5-phosphatases of for epithelial with stained cilia cells in sections expression in of kidney Normal disorganized NPHP4 patient tification (B) and of (C) (n=200). immunomicroscopy shorter of length Confocal expression appear ciliary patient. and abnormal cilia cilia ciliation and primary Primary of NPHP8 Quantification detect immunomicroscopy F) of to body. (E- Confocal antibodies basal Ac-tubulin sections. detect deletion. and kidney patient NPHP1 to Arl13b of with with IFT88 cells stained patient with sections tubular of and kidney cells renal patient tubular and in normal renal expression of in protein cilia Disorganized ciliary (A) abnormal with deletion. patient. NPHP1 cilia 2 deletion with = Disorganized NPHP1 patient bars the Scale 2. from cilia. cells decreased epithelial Fig. and kidney 200 membrane in tubular TBM (left) thickened and reveals = cilia TEM bars primary of Scale micrographs nephropathy. electron tubulointerstitial and disruption, elSi 127 Sci, Cell J 3,3830 doi:10.1016/j.devcel.2015.06.016 338-350. (3), urBo,19 Biol, Curr μ P 1,41-77 doi:10.1242/jcs.155275 4714-4727. 21), (Pt ;()mgie mgs40 images magnified (D) m; u o ee,18 Genet, Mol Hum uainJMd 45 Med, J Eurasian 1) 5655 doi:10.1016/j.cub.2009.05.025 R526-535. (13), ntRc(ooe) 291 (Hoboken), Rec Anat 2) 7142.doi:10.1093/hmg/ddp434 4711-4723. (24), 2,1811 doi:10.5152/eajm.2013.25 128-131. (2), μ .(ro,mrspiaycilia) primary marks (Arrow, m. 5 < .5wscniee ttsial significant. statistically considered was 0.05 9,17-08 doi:10.1002/ar.20754 1074-1078. (9), μ ;(ih)50 (right) m; μ m. elBo,216 Biol, Cell J μ eeomn,147 Development, .Transmission m. (1), Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. h,X,Gri,G,3d a eWge .C,MGry . aor .J,Dhry . etr J. Reiter, . . . D., Doherty, J., causes G. architecture Pazour, transition-zone R., ciliary McGorty, of C., disruption J. that syndrome. Weghe, reveals Joubert microscopy De cilia. Van Super-resolution mammalian 3rd, of (2017). (2011). G., F. function K. P. and Garcia, Jackson, structure X., of . Shi, Overview . (2007). . T. A., 69 S. E. Physiol, pathways. Christensen, Otto, and & J., P., genes M. Satir, disease Brauer, ciliopathy H., reveals R. doi:10.1016/j.cell.2011.04.019 network Giles, 513-528. C., protein (4), K. NPHP-JBTS-MKS retinal Corbit, the of J., form Mapping J. syndromic ciliopathy. Miller, a L., syndrome: a Sang, Senior-Loken (2012). - W. nephronophthisis. Baehr, with & syndrome associated S., dystrophy P. loken Bernstein, C., C. Senior- Ronquillo, (2014). doi:10.7860/JCDR/2014/9688.5120 compartment. H. ciliary R, the of gatekeepers proteins. of proteins: entry for NPHP doi:10.1083/jcb.201008080 gate (2019). ciliary (2010). the K. H. establish B. to Omran, Yoder, helps Targeted RPGRIP1L . 131 (2018). (2008). . Sci, zone. K. H. . S. Cell transition Dutcher, J., J Li, & cilia C. S., the Song, Guo, . E., H., for Lin, S. roles . Engle, type-specific J., M. . cell Croyle, doi:10.1096/fj.201801149R and Y., Z., 1440-1455. tissue- H. D. mice. reveal Revell, in Lu, L., mutations morphogenesis P., K. sperm Mks6 S. Bales, of R., steps Lee, later W. K., the Lewis, H. in defects Lin, 17 to Genet, E., due Mol infertility Wang, male Hum (2009). Y., causes S. Nphp1 Y. Schurmans, of Chiou, and disruption . human T., . in S. ciliopathies . 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(8), odSrn abPrpc il 9 Biol, Perspect Harb Spring Cold 1) 1818.doi:10.1038/ncb3599 1178-1188. (10), iinRs 75 Res, Vision 9,22-43 doi:10.1681/ASN.2005121351 2424-2433. (9), 6 89.doi:10.1016/j.visres.2012.07.003 88-97. , lnDanRs 8 Res, Diagn Clin J 2.doi:10.1101/cshperspect.a028134 (2). elBo,190 Biol, Cell J LSBo,18 Biol, PLoS AE ,33 J, FASEB 1) MD04-05. (11), 5,715-717. (5), nuRev Annu el 145 Cell, (3), (1), J Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. hu . to .A,Cuky . ii,R,Hr,T . hk,M,...Hlernt .(02.FAN1 (2012). F. 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Data may be preliminary. 8 Posted on Authorea 23 Aug 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159818272.20189241 — This a preprint and has not been peer reviewed. Data may be preliminary. 9