The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Petzold, Friederike; Billot, Katy; Chen, Xiaoyi; Henry, Charline; Filhol, Emilie; Martin, Yoann; Avramescu, Marina; Douillet, Maxime; Morinière, Vincent; Krug, Pauline; Jeanpierre, Marc; Tory, Kálmán; Boyer, Olivia; Burgun, Anita; Servais, Aude; Salomon, Rémi; Benmerah, Alexandre; Heidet, Laurence; Garcelon, Nicolas; Antignac, Corinne; Zaidan, Mohamad; Saunier, Sophie; Attié‐Bitach, Tania; Comier-Daire, Valerie; Rozet, Jean–Michel; Frishberg, Yaacov; Llanas, Brigitte; Broyer, M.; Mohsin, Nabil; Macher, Marie‐Alice; Philip, Nicole; Baudouin, Véronique; Brackman, D.; Loirat, Chantal; Charbit, Marina; Dehennault, Maud; Guyot, C.; Bataille, Pierre; Elting, Mariet W.; Deschênes, Georges; Gropman, Andrea; Guest, G.; Gagnadoux, Marie‐France; Nicoud, Philippe; Cochat, Pierre; Ranchin, Bruno; Bensman, A; Guerrot, Anne‐Marie; Knebelmann, Bertrand; Bilge, İlmay; Daniele, Bruno; Burtey, Stéphane; Rouviere, Clement; Caudwell, Valérie; Morin, Denis; Dollfus, Hélène; Maisin, Anne; Hamel, Christian; Bieth, Éric; Gié, Sophie; Goodship, Judith A.; Roussey, G.; Selve, H. La; Nivet, Hubert; Bessenay, Lucie; Caillez, Mathilde; Palcoux, J. B.; Benoit, Stéphane L.; Dubot, P; Fila, Marc; Giuliano, Fabienne; Iftene, Daouya; Kessler, Michèle; Kwon, Thérèsa; Lahoche, Annie; Laurent, Audrey; Leclerc, Anne-Laure; Milford, David V.; Neuhaus, Thomas J.; Odent, Sylvie; Eckart, P.; Chauveau, Dominique; Niaudet, Patrick; Repetto, Horacio A.; Taque, Sophie; Bruel, Alexandra; Noel-Botte, Alexandra; Launay, Emma Allain; Allard, Lise; Anlicheau, Dany; Adra, A; Garnier, Arnaud; Nagra, Arvind; Baatard, Remy; Bacchetta, Justine; Sadikoglu, Banu; Barnérias, Christine; Barthélémy, Anne; Basel, Lina; Bassilios, Nader; Maı̈z, H. Ben; Moussa, F. Ben; Benmati, Faïza; Berthaud, Romain; Bertholet, Aurélia; Blanchier, Dominique; Boffa, J.J.; Bouchireb, Karim; Bouhabel, Ihab; Boukerroucha, Zakaria; Bourdat-Michel, Guylhène; Boute, Odile; Brochard, Karine; Caumes, Roseline; Elalaoui, Siham Chafai; Chamontin, B.; Chastang, Marie Caroline; Piètrement, Christine; Richer, Christine; Legendre, Christophe; Dahan, Karin; Dalla‐Vale, Fabienne; Thibaudin, Damien; Dauvergne, M.; Davourie, Salandre; DeBeukelaer, Martin M.; Delbet, Jean Daniel; Deltas, Constantinos; Graber, D; Devillars, Nadège; Diouf, Boucar; Fenzy, Martine Doco; André, Jean-Luc; Joly, Dominique; Fryer, Alan; Albano, Laetitia; Cassuto, Élisabeth; Pinçon, A.; Medeira, Ana; Chaussenot, Annabelle; Mensire-Marinier, Anne; Bouissou, F; Decramer, Stéphane; Bottani, Armand; Hummel, Aurélie; Karras, Alexandre; Katz, Amitai; Azéma, Christine; Janbon, Bénédicte; Roussel, Bernard; Bonniol, Claude; Mariat, Christophe; Champion, G.; Chantreuil, Deborah; Chassaing, Nicolas; Mousson, Christiane; Baudeau, Christine; Cuntz, Delphine Hafdar; Mignot, Cyril; Dehoux, Laurène; Lacombe, Didier; Hannedouche, Thierry; Mérieau, Elodie; Charlin, Emmanuelle; Gauthier, Eric; Plasse, Florent; Faguer, Stanislas; Lebas, Fanny; Démurger, Florence; Emma, Francesco; Cartault, François; Dumont, Geneviève; Godefroid, Nathalie; Guigonis, Vincent; Hillaire, Sophie; Groothoff, Jaap W.; Dudley, Jan; Jourde-Chiche, Noémie; Karoui, Khalil El; Krid, Saoussen; Coudert, Krier; Bencheick, Larbi; Yver, L; Lavocat, Marie-Pierre; Sagazan, Le Monies De; Leroy, Valérie; Thibaudin, Lise; Ingulli, Liz; Gwanmesia, Lorraine; Bürglen, Lydie; Saïd-Menthon, Marie-Hélène; Carrera, Marta; Nizon, Mathilde; Melander, Catherine; Foulard, M; Blayo, Monique; Prinseau, J; Jay, Nadine; Brun, Nathalie; Camille, Nicolas; Nobili, François; Devuyst, Olivier; Brahim, Ouafa Ben; Parvex, Paloma; Sabourin, Luc A.; Blanc, Philippe; Vanhille, Philippe; Galichon, Pierre; Pierrepont, Sophie; Planquois, Vincent; Poussard, Gwenaelle; Noble, Claire Pouteil; Allal, Radia; Bernard, R.; Mounet, Raynaud; Cahen, R; Touraine, Renaud; Rigothier, Claire; Ryckewaert, A.; Sacquépée, M.; Chehadeh, Salima El; Samaille, Charlotte; Haq, Shuman; Simckes, Ari M.; Lanoiselée, S.; Tellier, Stéphanie; Subra, Jean‐François; Cloarec, Sylvie; Tenenbam, Julie; Lamy, T.; Garraud, Valérie Drouin; Valette, H.; Meyssonnier, Vanina; Vargas‐Poussou, Rosa; Snajer, Yves; Durault, Sandrine; Plaisier, Emmanuelle; Bérard, Étienne; Fakhouri, Fádi; Louillet, Férielle; Finielz, Paul; Fischbach, Michel; Foliguet, B; Francois-Pradier, Hélène; Garaix, Florentine; Gérard, Marion; Rizzoni, Gianfranco; Gilbert, Brigitte; Glotz, Denis; Dubrasquet, Astrid Godron; Grünfeld, Jean‐Pierre; Bollée, Guillaume; Hall, Michelle; Hansson, Sverker; Haye, Damien; Taffin, Hélène; Hildebrandt, Friedhelm; Hourmand, M; Kayserili, Hülya; Tack, Ivan; Jacquemont, Marie Line; Fabre-Teste, Jennifer; Kashtan, Clifford E.; Hoeck, K Van; Klein, Alexandre; Knefati, Yannick; Knoers, Nine V A M; Konrad, Martin; Lachaux, Alain; Landru, Isabelle; Landthaler, Gilbert; Lang, Philippe; Pogamp, P. Le; Legris, Tristan; Didailler, Catherine; Lobbedez, Thierry; Parscau, L. De; Pinson, Lucile; Maheut, Hervé; Duval-Arnould, Marc; Rio, Marlène; Gübler, Marie-Claire; Merville, Pierre; Mestrallet, G; Meunier, M.; Moreau, Karine; Harambat, Jérôme; Morgan, Graeme; Mourad, Georges; Stuber, Niksic; Boespflug‐Tanguy, Odile; Dunand, Olivier; Niel, Olivier; Ouali, Nacéra; Malvezzi, Paolo; Jaoude, Pauline Abou; Pelletier, Solenne; Peltier, Julie; Petersen, Michael B.; Michel, P.; Rémy, Philippe; Philit, Jean‐Baptiste; Pichault, Valérie; Villemeur, Thierry Billette de; Boudailliez, B; Leheup, Bruno; Dossier, Claire; Djeddi, Djamal-Dine; Berland, Yvon; Ligny, Bruno Hurault de; Rigden, Susan P. A.; Robino, Christophe; Rossi, Annick; Sarnacki, Sabine; Saïdani, Messaoud; Sartorius, Albane; Schäfer, Eberhard; Laszlo, Sztriha; Thouret, Marie-Christine; Thuillier-Lecouf, A.; Trachtman, Howard; Trivin, Claire; Tsimaratos, Michel; Damme‐Lombaerts, Rita Van; Willems, Marjolaine; Youssef, Michel; Zaloszyc, Ariane; Zawodnik, A; Ziliotis, Marie-Julia

doi:10.1016/j.kint.2023.05.007

Cited by 16 publications

(13 citation statements)

References 43 publications

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“…NPHP1 accounts for 20-50% of all genetically solved NPHP cases ( 153 – 155 ). About one-third of NPHP1 cases are syndromic, often presenting with Senior-Løken syndrome, SLS (retinal degeneration) and Joubert syndrome, JS (cerebellar and oculomotor anomalies) ( 156 ). Currently, more than 25 genes have been identified as genetic causes of NPHP ( 155 , 157 ).…”

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

“…Some NPHP proteins are directly involved in forming the basal body as well as facilitating its migration and docking to the cell membrane ( 158 ). Interestingly, many NPHP proteins involved in ciliopathies with either kidney or eye involvement cluster within the transition zone modules ( 156 ). The inappropriate accumulation of non-ciliary proteins in the cilium proper due to aberrant ciliary gating is hypothesized to contribute to disrupted ciliary function in NPHP and other renal ciliopathies ( 159 ).…”

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

“…Approximately 10% of syndromic NPHP cases present with skeletal anomalies often found alongside liver, eye, and CNS anomalies ( 156 ). Short-rib thoracic dysplasia with and without polydactyly (SRTD) are a group of skeletal ciliopathy disorders with shared features of polydactyly, shortening of the long bones and severe rib and thoracic malformations ( 152 , 195 ).…”

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

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Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

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Ciliopathies are a group of rare genetic disorders caused by defects to the structure or function of the primary cilium. They often affect multiple organs, leading to brain malformations, congenital heart defects, and anomalies of the retina or skeletal system. Kidney abnormalities are among the most frequent ciliopathic phenotypes manifesting as smaller, dysplastic, and cystic kidneys that are often accompanied by renal fibrosis. Many renal ciliopathies cause chronic kidney disease and often progress to end-stage renal disease, necessitating replacing therapies. There are more than 35 known ciliopathies; each is a rare hereditary condition, yet collectively they account for a significant proportion of chronic kidney disease worldwide. The primary cilium is a tiny microtubule-based organelle at the apex of almost all vertebrate cells. It serves as a “cellular antenna” surveying environment outside the cell and transducing this information inside the cell to trigger multiple signaling responses crucial for tissue morphogenesis and homeostasis. Hundreds of proteins and unique cellular mechanisms are involved in cilia formation. Recent evidence suggests that actin remodeling and regulation at the base of the primary cilium strongly impacts ciliogenesis. In this review, we provide an overview of the structure and function of the primary cilium, focusing on the role of actin cytoskeleton and its regulators in ciliogenesis. We then describe the key clinical, genetic, and molecular aspects of renal ciliopathies. We highlight what is known about actin regulation in the pathogenesis of these diseases with the aim to consider these recent molecular findings as potential therapeutic targets for renal ciliopathies.

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Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

Section: Renal Ciliopathies: Molecular Mechanisms Of Disease and Acti...mentioning

confidence: 99%

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Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

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“…Nephronophthisis (NPH) is an autosomal recessive tubulo-interstitial nephropathy that accounts for up to 15% of end stage kidney disease (ESKD) in children ( Hamiwka et al, 2008 ; Salomon et al, 2009 ). The juvenile form is the most prevalent (48%) and progresses to ESKD before the age of 15 ( Hildebrandt et al, 2009 ; Petzold et al, 2023 ). Typical clinical symptoms are polyuria, polydipsia with regular fluid intake, impaired sodium reabsorption leading to hypovolemia and hyponatremia, anemia and growth retardation ( König et al, 2017 ; Stokman et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…Histologically, it is characterized by a thickening of the tubular basement membranes and a massive, diffuse interstitial fibrosis, accompanied by the appearance of tubular cysts at the cortico-medullary junction ( Hildebrandt et al, 2009 ). In about 50% of cases, patients with NPH have extrarenal manifestations defining specific syndromic forms ( Petzold et al, 2023 ). To date, mutations in more than 20 different genes have been identified to cause NPH ( Braun and Hildebrandt, 2017 ; Devlin and Sayer, 2019 ; Petzold et al, 2023 ), the major ones being NPHP1 and NPHP4 genes, which account for 53% and 5% of cases, respectively ( Petzold et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Fluid shear stress triggers cholesterol biosynthesis and uptake in inner medullary collecting duct cells, independently of nephrocystin-1 and nephrocystin-4

Garfa Traoré,

Roccio,

Miceli

et al. 2023

Front. Mol. Biosci.

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Renal epithelial cells are subjected to fluid shear stress of urine flow. Several cellular structures act as mechanosensors–the primary cilium, microvilli and cell adhesion complexes–that directly relay signals to the cytoskeleton to regulate various processes including cell differentiation and renal cell functions. Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy leading to end-stage kidney failure before adulthood. NPHP1 and NPHP4 are the major genes which code for proteins that form a complex at the transition zone of the primary cilium, a crucial region required for the maintenance of the ciliary composition integrity. These two proteins also interact with signaling components and proteins associated with the actin cytoskeleton at cell junctions. Due to their specific subcellular localization, we wondered whether NPHP1 and NPHP4 could ensure mechanosensory functions. Using a microfluidic set up, we showed that murine inner medullary collecting ductal cells invalidated for Nphp1 or Nphp4 are more responsive to immediate shear exposure with a fast calcium influx, and upon a prolonged shear condition, an inability to properly regulate cilium length and actin cytoskeleton remodeling. Following a transcriptomic study highlighting shear stress-induced gene expression changes, we showed that prolonged shear triggers both cholesterol biosynthesis pathway and uptake, processes that do not seem to involve neither NPHP1 nor NPHP4. To conclude, our study allowed us to determine a moderate role of NPHP1 and NPHP4 in flow sensation, and to highlight a new signaling pathway induced by shear stress, the cholesterol biosynthesis and uptake pathways, which would allow cells to cope with mechanical stress by strengthening their plasma membrane through the supply of cholesterol.

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The dominant findings of a recessive man: from Mendel’s kid pea to kidney

Tory

2023

Pediatr Nephrol

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The research of Mendel, born two centuries ago, still has many direct implications for our everyday clinical work. He introduced the terms “dominant” and “recessive” characters and determined their 3:1 ratio in the offspring of heterozygous “hybrid” plants. This distribution allowed calculation of the number of the phenotype-determining “elements,” i.e., the alleles, and has been used ever since to prove the monogenic origin of a disorder. The Mendelian inheritance of monogenic kidney disorders is still of great help in distinguishing them from those with multifactorial origin in clinical practice. Inheritance of most monogenic kidney disorders fits to Mendel’s observations: the equal contribution of the two parents and the complete penetrance or the direct correlation between the frequency of the recessive character and the degree of inbreeding. Nevertheless, beyond the truth of these basic concepts, several observations have expanded their genetic characteristics. The extreme genetic heterogeneity, the pleiotropy of the causal genes and the role of modifiers in ciliopathies, the digenic inheritance and parental imprinting in some tubulopathies, and the incomplete penetrance and eventual interallelic interactions in podocytopathies, reflect this expansion. For all these reasons, the transmission pattern in a natural setting may depend not only on the “character” but also on the causal gene and the variant. Mendel’s passion for research combined with his modest personality and meticulous approach can still serve as an example in the work required to understand the non-Mendelian universe of genetics.

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The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Cited by 16 publications

References 43 publications

Primary cilia and actin regulatory pathways in renal ciliopathies

Primary cilia and actin regulatory pathways in renal ciliopathies

Fluid shear stress triggers cholesterol biosynthesis and uptake in inner medullary collecting duct cells, independently of nephrocystin-1 and nephrocystin-4

The dominant findings of a recessive man: from Mendel’s kid pea to kidney

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