ZFIN ID: ZDB-LAB-160309-1
Saunier's lab
PI/Director: Saunier, Sophie
Contact Person: Delous, Marion
Email: marion.delous@inserm.fr
URL: http://www.institutimagine.org/en/research/23-research-labs/118-molecular-bases-of-hereditary-kidney-diseases-nephronopthisis-and-hypodysplasia.html
Address: Imagine Institute - Inserm U1163 24 Boulevard du Montparnasse 75015 Paris France
Country: France
Phone: +33 1 42 75 43 41
Fax: +33 1 42 75 42 05
Line Designation: ii

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Our research aims at unraveling the pathogenesis of nephronophthisis (NPH) and renal hypodysplasia (RHD), two major genetic causes of renal insufficiency in children. Nephronophthisis (NPH) is an autosomal recessive nephropathy, characterized by interstitial fibrosis and formation of tubular cysts, which represents the most common genetic cause of end-stage renal disease in children. NPH can be isolated or associated with extra-renal anomalies including retinal dystrophy, cerebellar vermis hypoplasia, skeletal dysmorphisms and/or situs inversus. The specific association of these anomalies defines complex syndromes now called “ciliopathies”. Renal hypodysplasia (RHD) is a phenotypically heterogeneous disorder that encompasses a spectrum of kidney development defects including renal agenesis, hypoplasia (defect in the number of nephrons) and dysplasia with or without cysts. It is also one of the most frequent cause of end-stage renal disease in children and the most severe forms (bilateral renal agenesis and multicystic dysplasia) are diagnosed in utero and justify medical termination of pregnancy. During the past 15 years, our group has participated in the identification of mutations in 10 out of the 18 genes that cause NPH (either isolated or syndromic forms), and the demonstration that most of the proteins encoded by these genes, nephrocystins (NPHP) and intraflagellar transport components (IFTA and IFTB), are localized at the primary cilium. This ubiquitous and conserved microtubule-based structure is found at the apical membrane of kidney epithelial cells where it functions as a flow mechano/chemo-sensor to mediate signals that regulate morphogenesis of kidney tubules and tissue homeostasis, thus preventing cysts formation. Our recent work based on the use of in vitro kidney epithelial cell models, patient fibroblasts and in vivo models including mouse and zebrafish, demonstrated that the NPHP and IFT proteins are critical for ciliary function, cell polarity and epithelial morphogenesis.

Ryan, Rebecca Post-Doc de Tomasi, Lara Graduate Student Dupont, Marie Graduate Student
Garcia, Hugo Graduate Student Delous, Marion Research Staff

Dupont, M.A., Humbert, C., Huber, C., Siour, Q., Guerrera, I.C., Jung, V., Christensen, A., Pouliet, A., Garfa-Traore, M., Nitschké, P., Injeyan, M., Millar, K., Chitayat, D., Shannon, P., Girisha, K.M., Shukla, A., Mechler, C., Lorentzen, E., Benmerah, A., Cormier-Daire, V., Jeanpierre, C., Saunier, S., Delous, M. (2019) Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion. Human molecular genetics. 28(16):2720-2737
Reilly, M.L., Stokman, M.F., Magry, V., Jeanpierre, C., Alves, M., Paydar, M., Hellinga, J., Delous, M., Pouly, D., Failler, M., Martinovic, J., Loeuillet, L., Leroy, B., Tantau, J., Roume, J., Evans, C.G., Shan, X., Filges, I., Allingham, J.S., Kwok, B.H., Saunier, S., Giles, R.H., Benmerah, A. (2018) Loss of function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish. Human molecular genetics. 28(5):778-795
Ryan, R., Failler, M., Reilly, M.L., Garfa-Traore, M., Delous, M., Filhol, E., Reboul, T., Bole-Feysot, C., Nitschké, P., Baudouin, V., Amselem, S., Escudier, E., Legendre, M., Benmerah, A., Saunier, S. (2017) Functional characterization of tektin-1 in motile cilia and evidence for TEKT1 as a new candidate gene for motile ciliopathies. Human molecular genetics. 27(2):266-282
Macia, M.S., Halbritter, J., Delous, M., Bredrup, C., Gutter, A., Filhol, E., Mellgren, A.E., Leh, S., Bizet, A., Braun, D.A., Gee, H.Y., Silbermann, F., Henry, C., Krug, P., Bole-Feysot, C., Nitschké, P., Joly, D., Nicoud, P., Paget, A., Haugland, H., Brackmann, D., Ahmet, N., Sandford, R., Cengiz, N., Knappskog, P.M., Boman, H., Linghu, B., Yang, F., Oakeley, E.J., Saint Mézard, P., Sailer, A.W., Johansson, S., Rødahl, E., Saunier, S., Hildebrandt, F., Benmerah, A. (2017) Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis. American journal of human genetics. 100:1-11
Grampa, V., Delous, M., Zaidan, M., Odye, G., Thomas, S., Elkhartoufi, N., Filhol, E., Niel, O., Silbermann, F., Lebreton, C., Collardeau-Frachon, S., Rouvet, I., Alessandri, J.L., Devisme, L., Dieux-Coeslier, A., Cordier, M.P., Capri, Y., Khung-Savatovsky, S., Sigaudy, S., Salomon, R., Antignac, C., Gubler, M.C., Benmerah, A., Terzi, F., Attié-Bitach, T., Jeanpierre, C., Saunier, S. (2016) Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation. PLoS Genetics. 12:e1005894
Bizet, A.A., Becker-Heck, A., Ryan, R., Weber, K., Filhol, E., Krug, P., Halbritter, J., Delous, M., Lasbennes, M.C., Linghu, B., Oakeley, E.J., Zarhrate, M., Nitschké, P., Garfa-Traore, M., Serluca, F., Yang, F., Bouwmeester, T., Pinson, L., Cassuto, E., Dubot, P., Elshakhs, N.A., Sahel, J.A., Salomon, R., Drummond, I.A., Gubler, M.C., Antignac, C., Chibout, S., Szustakowski, J.D., Hildebrandt, F., Lorentzen, E., Sailer, A.W., Benmerah, A., Saint-Mezard, P., Saunier, S. (2015) Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization. Nature communications. 6:8666
Halbritter, J., Bizet, A.A., Schmidts, M., Porath, J.D., Braun, D.A., Gee, H.Y., McInerney-Leo, A.M., Krug, P., Filhol, E., Davis, E.E., Airik, R., Czarnecki, P.G., Lehman, A.M., Trnka, P., Nitschké, P., Bole-Feysot, C., Schueler, M., Knebelmann, B., Burtey, S., Szabó, A.J., Tory, K., Leo, P.J., Gardiner, B., McKenzie, F.A., Zankl, A., Brown, M.A., Hartley, J.L., Maher, E.R., Li, C., Leroux, M.R., Scambler, P.J., Zhan, S.H., Jones, S.J., Kayserili, H., Tuysuz, B., Moorani, K.N., Constantinescu, A., Krantz, I.D., Kaplan, B.S., Shah, J.V., Hurd, T.W., Doherty, D., Katsanis, N., Duncan, E.L., Otto, E.A., Beales, P.L., Mitchison, H.M., Saunier, S., and Hildebrandt, F. (2013) Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans. American journal of human genetics. 93(5):915-925
Hoff, S., Halbritter, J., Epting, D., Frank, V., Nguyen, T.M., van Reeuwijk, J., Boehlke, C., Schell, C., Yasunaga, T., Helmstädter, M., Mergen, M., Filhol, E., Boldt, K., Horn, N., Ueffing, M., Otto, E.A., Eisenberger, T., Elting, M.W., van Wijk, J.A., Bockenhauer, D., Sebire, N.J., Rittig, S., Vyberg, M., Ring, T., Pohl, M., Pape, L., Neuhaus, T.J., Elshakhs, N.A., Koon, S.J., Harris, P.C., Grahammer, F., Huber, T.B., Kuehn, E.W., Kramer-Zucker, A., Bolz, H.J., Roepman, R., Saunier, S., Walz, G., Hildebrandt, F., Bergmann, C., and Lienkamp, S.S. (2013) ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nature Genetics. 45(8):951-6
Delous, M., Yin, C., Shin, D., Ninov, N., Debrito Carten, J., Pan, L., Ma, T.P., Farber, S.A., Moens, C.B., and Stainier, D.Y. (2012) sox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development. PLoS Genetics. 8(6):e1002754