Skip to Main content Skip to Navigation
Journal articles

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Joery den Hoed 1 Elke de Boer Norine Voisin Alexander J.M. Dingemans Nicolas Guex 2 Laurens Wiel Christoffer Nellaker Shivarajan Amudhavalli 3 Siddharth Banka 4 Frederique Bena Bruria Ben-Zeev Vincent Bonagura Ange-Line Bruel 5, 6 Theresa Brunet Han Brunner Hui Chew Jacqueline Chrast Loreta Cimbalistienė Hilary Coon Emmanuèlle Délot Florence Démurger Anne-Sophie Denommé-Pichon 6, 5 Christel Depienne Dian Donnai David Dyment Orly Elpeleg Laurence Faivre 6, 5 Christian Gilissen Leslie Granger Benjamin Haber Yasuo Hachiya Yasmin Hamzavi Abedi Jennifer Hanebeck Jayne Hehir-Kwa Brooke Horist Toshiyuki Itai Adam Jackson Rosalyn Jewell Kelly Jones Shelagh Joss Hirofumi Kashii Mitsuhiro Kato Anja Kattentidt-Mouravieva Fernando Kok Urania Kotzaeridou Vidya Krishnamurthy Vaidutis Kučinskas Alma Kuechler Alinoë Lavillaureix 7, 8, 9 Pengfei Liu Linda Manwaring Naomichi Matsumoto Benoît Mazel Kirsty Mcwalter Vardiella Meiner Mohamad Mikati Satoko Miyatake Takeshi Mizuguchi Lip Moey Shehla Mohammed Hagar Mor-Shaked Hayley Mountford Ruth Newbury-Ecob Sylvie Odent 7, 8, 9 Laura Orec Matthew Osmond Timothy Palculict Michael Parker Andrea Petersen Rolph Pfundt Eglė Preikšaitienė Kelly Radtke Emmanuelle Ranza Jill Rosenfeld Teresa Santiago-Sim Caitlin Schwager Margje Sinnema Lot Snijders Blok Rebecca Spillmann Alexander P.A. Stegmann Isabelle Thiffault Linh Tran Adi Vaknin-Dembinsky Juliana Vedovato-Dos-Santos Samantha Schrier Vergano Eric Vilain Antonio Vitobello Matias Wagner Androu Waheeb Marcia Willing Britton Zuccarelli Usha Kini Dianne Newbury Tjitske Kleefstra Alexandre Reymond Simon Fisher 1, 10, * Lisenka E.L.M. Vissers 10
Abstract : 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.
Document type :
Journal articles
Complete list of metadata

https://hal-univ-rennes1.archives-ouvertes.fr/hal-03268683
Contributor : Laurent Jonchère <>
Submitted on : Wednesday, June 23, 2021 - 1:37:36 PM
Last modification on : Thursday, June 24, 2021 - 3:39:37 AM

Links full text

Identifiers

Citation

Joery den Hoed, Elke de Boer, Norine Voisin, Alexander J.M. Dingemans, Nicolas Guex, et al.. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. American Journal of Human Genetics, Elsevier (Cell Press), 2021, 108 (2), pp.346-356. ⟨10.1016/j.ajhg.2021.01.007⟩. ⟨hal-03268683⟩

Share

Metrics

Record views

17