Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
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den Hoed, Joery | de Boer, Elke | Voisin, Norine | Dingemans, Alexander J.M. | Guex, Nicolas | Wiel, Laurens | Nellaker, Christoffer | Amudhavalli, Shivarajan | Banka, Siddharth | Bena, Frederique | Ben-Zeev, Bruria | Bonagura, Vincent | Bruel, Ange-Line | Brunet, Theresa | Brunner, Han | Chew, Hui | Chrast, Jacqueline | Cimbalistienė, Loreta | Coon, Hilary | Délot, Emmanuèlle | Démurger, Florence | Denommé-Pichon, Anne-Sophie | Depienne, Christel | Donnai, Dian | Dyment, David | Elpeleg, Orly | Faivre, Laurence | Gilissen, Christian | Granger, Leslie | Haber, Benjamin | Hachiya, Yasuo | Abedi, Yasmin Hamzavi | Hanebeck, Jennifer | Hehir-Kwa, Jayne | Horist, Brooke | Itai, Toshiyuki | Jackson, Adam | Jewell, Rosalyn | Jones, Kelly | Joss, Shelagh | Kashii, Hirofumi | Kato, Mitsuhiro | Kattentidt-Mouravieva, Anja | Kok, Fernando | Kotzaeridou, Urania | Krishnamurthy, Vidya | Kučinskas, Vaidutis | Kuechler, Alma | Lavillaureix, Alinoë | Liu, Pengfei | Manwaring, Linda | Matsumoto, Naomichi | Mazel, Benoît | Mcwalter, Kirsty | Meiner, Vardiella | Mikati, Mohamad | Miyatake, Satoko | Mizuguchi, Takeshi | Moey, Lip | Mohammed, Shehla | Mor-Shaked, Hagar | Mountford, Hayley | Newbury-Ecob, Ruth | Odent, Sylvie | Orec, Laura | Osmond, Matthew | Palculict, Timothy | Parker, Michael | Petersen, Andrea | Pfundt, Rolph | Preikšaitienė, Eglė | Radtke, Kelly | Ranza, Emmanuelle | Rosenfeld, Jill | Santiago-Sim, Teresa | Schwager, Caitlin | Sinnema, Margje | Snijders Blok, Lot | Spillmann, Rebecca | Stegmann, Alexander P.A. | Thiffault, Isabelle | Tran, Linh | Vaknin-Dembinsky, Adi | Vedovato-Dos-Santos, Juliana | Schrier Vergano, Samantha | Vilain, Eric | Vitobello, Antonio | Wagner, Matias | Waheeb, Androu | Willing, Marcia | Zuccarelli, Britton | Kini, Usha | Newbury, Dianne | Kleefstra, Tjitske | Reymond, Alexandre | Fisher, Simon | Vissers, Lisenka E.L.M.
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CCSD ; Elsevier (Cell Press) -
International audience.
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
