MedElevator Войти в исследования
← Поиск публикаций
medRxiv : the preprint server for health sciences · 2026

Clinical, in vitro, and in vivo evidence of WAPL as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder.

СтатьяПрепринтНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…

История · было → стало

Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.

Boone Philip M, Erdin Serkan, Mohamed Abucar, Haghshenas Sadegheh, Faour Kamli N W, Kao Emeline, Fu Jack, Auwerx Chiara, Harripaul Ricardo, Jana Bimal, Springer Danielle, Hallstrom Grey, de Esch Celine E F, Denhoff Erica, Holmes Lauren, Mohajeri Kiana, Lemanski John, Kerkhof Jennifer, McConkey Haley, Rzasa Jessica, McCune Madison J, Levy Michael A, Grafstein Julia, Larson Matthew, Wright Zsabre, Beauchamp Roberta L, Lucente Diane, Jamra Rami Abou, Agrawal Neena, Agrawal Pankaj, Andersen Erica F, Argilli Emanuela, Araiza Renee, Ballal Sonia, Baxter Megan F, Bergant Gaber, Bertsche Astrid, Bhavsar Riya, Bortola Debora R, Bothe Viktoria, Brasch-Andersen Charlotte, Braun Dominique, Bruel Ange-Line, Buchanan Catherine, Burt Nicholas D, Carvalho Laura M L, Chiriatti Luigi, Cogne Benjamin, Collins Ryan, Crunk Amy, Currall Benjamin, Delahaye-Duriez Andree, Delanne Julian, Denommé-Pichon Anne-Sophie, Devriendt Koenraad, Domingo Aloysius, Duncan Laura, Faivre Laurence, Famularo Laura, Fulton Anne, Genetti Casie, Harel Tamar, Havlovicova Marketa, Higgs Jenny, Houlier Marine, Iascone Maria, Immken LaDonna, Isidor Bertrand, Kaiser Frank J, Karbone Kaycee, Kenna Margaret, Khan Amjad, Kimmig Lara Kristina, Kleefstra Tjitske, Kraus Eva-Maria, Krepischi Ana C V, Krey Ilona, Ladda Roger, Lanoue Louise, Le Caignec Cedric, Lewis Zoe K, Lima Gloria, Lynch Sally Ann, Macek Milan, Maier Olivier, Maitz Silvia, Male Alison, Malikova Marcela, McKay Victoria, Moldovan Oana, Monteil Danielle, Oliveira Mariana Moysés, Munasinghe Jeeva, Nakamori Sachiko, Neuser Sonja, Nizon Mathilde, Nuttle Xander, O'Keefe Kathryn, Orec Laura, Parenti Ilaria, Peterlin Borut, Pfundt Rolph, Pouncey Jill, Radio Francesca Clementina, Robert Leema, Rodan Lance, Rosenberg-Fogler Hallel, Rosenfeld Jill A, Safraou Hana, Salani Monica, Schliesske Sophia, Seaby Eleanor G, Sell Susan, Eliot Shearer A, Sherr Elliott, Shillington Amelle, Siebold Dorothea, Sinnema Margje, Smith Laura, Stegmann Alexander P A, Stevens Cathy, Stevens Servi, Surette Eric, Tartaglia Marco, Taylor Jenny C, Thompson Michelle L, Tørring Pernille M, Mau Them Frederic Tran, Tsoulaki Olga, Umair Muhammad, Vanhoutte Els, Vincent Marie, Vitobello Antonio, von Wintzingerode Lydia, Watt Amy, Wayhelova Marketa, Wentzensen Ingrid M, Wilson William, Wojcik Monica H, Yuan Bo, Zampino Giuseppe, Srivastava Siddharth, Westphal Dominik S, Riedhammer Korbinian M, Joyce Eric, Yadav Rachita, Gusella James, Tai Derek J C, Sadikovic Bekim, Pfeifer Karl E, Talkowski Michael E

Аннотация

Cohesin is a fundamental genome-organizing complex that orchestrates three-dimensional chromosome folding and gene expression via DNA loop extrusion. Alterations to genes encoding cohesin subunits and cohesin loaders cause Mendelian disorders, including Cornelia de Lange syndrome (CdLS). By contrast, disruption of factors that remove cohesin from DNA, including WAPL and its binding partners PDS5A and PDS5B, have not yet been associated with human disease. Here, we explored the relevance of these cohesin release factors in Mendelian disease by establishing a rare disease cohort of deeply phenotyped individuals with heterozygous, predicted damaging variants in WAPL (n=27), PDS5A (n=8), and PDS5B (n=8), by modeling WAPL deficiency in human cell lines and mice, and by aggregating rare disease association statistics from consortia studies. We identified a WAPL-related disorder characterized by developmental delay, intellectual disability, and risk of other developmental anomalies including clubfoot. Similarities between individuals with damaging WAPL variants and those with large, recurrent 10q22.3q23.2 (10q) deletions (which encompass WAPL) nominate WAPL as a driver gene within this genomic disorder region. While carriers of PDS5A or PDS5B variants exhibited features of developmental disorders, neither cohort-based statistics nor case phenotyping associated these genes with specific phenotypes. We used CRISPR engineering to generate truncating variants in WAPL, as well the 7.8 Mb 10q deletion or duplication in human iPSCs and induced neurons. Transcriptomic analyses identified differentially expressed genes in both models, with highly significant overlap between WAPL haploinsufficiency and 10q deletion signatures. Mice with 50% residual Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl expression displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity. In summary, we delineated a novel genetic condition caused by cohesin release factor deficiency, nominated WAPL as a driver gene within a genomic disorder region, and further illuminated dosage sensitivity of human cohesin.