Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14

作者：Adam Jackson, Sheng‐Jia Lin, Elizabeth A. Jones, Kate Chandler, David Orr, Celia Moss, Z. Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Hewitt Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon C. Lovell, Konstantina Drosou, John C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C. R. Boustred, H. Brittain, Myles Brown, Mark J. Caulfield, Gcf Chan, Adam Giess, John N. Griffin, A. Hamblin, S. A. Henderson, Tim Hubbard, R. Jackson, J. Louise Jones, D. Kasperaviciute, M. Kayikci, Athanasios Kousathanas, L. Lahnstein, A. Lakey, S. E. A. Leigh, I. U. S. Leong, Fabrice Lopez, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, J. Mitchell, L. Moutsianas, M. Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Christopher A. Odhams, C. Patch, D. Perez-Gil, Mariana Buongermino Pereira, J. Pullinger, T. Rahim, Álvaro Rendón, T. Rogers, K. Savage, K. Sawant, Roy Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, Ana Lisa Taylor Tavares, Elizabeth R. Thomas, Simon R. Thompson, Arianna Tucci, M. J. Welland, E. Williams, K. Witkowska, S. M. Wood, Magdalena Zarowiecki, Olaf Rieß, T. Haack, Holm Graeßner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze‐Hentrich, Rebecca Schüle, Christoph Keßler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Lüdger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Šablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldız, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, C. Marini Bettolo, Sabine Specht, Jill Clayton‐Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne‐Sophie Denommé‐Pichon, Yannis Duffourd, Émilie Tisserant, Ange‐Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltrán, Marta Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvò, Carles García, Marcos Fernández-Callejo, Carles Hernandéz-Ferrer, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros‐Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stévanin, Alexandra Dürr, Claire-Sophie Davoine, Léna Guillot‐Noël, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Métay, B. Eymard, Enzo Cohen, António Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Věra Franková, Markéta Havlovičová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Daniš, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcová, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter De Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, José Garcia‐Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloès, Séverine Drunat, Caroline Rooryck, Aurélien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada de la Paz, Eva Bermejo, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Péter Balicza, Mária Judit Molnár, Aleš Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje G. Pauly, Alfons Macaya, Anna Marcé‐Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodríguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horváth, Gabriel Capellá, Laura Valle, Elke Holinski‐Feder, Andreas Laner, Verena Steinke‐Lange, Evelin Schröck, Andreas Rump, Gaurav K. Varshney, Siddharth Banka · 发表于：Human Genetics and Genomics Advances · 年份：2023 · DOI：10.1016/j.xhgg.2023.100186 · 被引用次数：12 · 研究领域：dental development and anomalies、Bone and Dental Protein Studies、Connexins and lens biology

TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear ...