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den Hoed, J.* ; de Boer, E.* ; Voisin, N.* ; Dingemans, A.J.M.* ; Guex, N.* ; Wiel, L.* ; Nellaker, C.* ; Amudhavalli, S.M.* ; Banka, S.* ; Bena, F.S.* ; Ben-Zeev, B.* ; Bonagura, V.R.* ; Bruel, A.L.* ; Brunet, T.* ; Brunner, H.G.* ; Chew, H.B.* ; Chrast, J.* ; Cimbalistienė, L.* ; Coon, H.* ; Délot, E.C.* ; Démurger, F.* ; Denommé-Pichon, A.S.* ; Depienne, C.* ; Donnai, D.* ; Dyment, D.A.* ; Elpeleg, O.* ; Faivre, L.* ; Gilissen, C.* ; Granger, L.* ; Haber, B.* ; Hachiya, Y.* ; Abedi, Y.H.* ; Hanebeck, J.* ; Hehir-Kwa, J.Y.* ; Horist, B.* ; Itai, T.* ; Jackson, A.* ; Jewell, R.* ; Jones, K.L.* ; Joss, S.* ; Kashii, H.* ; Kato, M.* ; Kattentidt-Mouravieva, A.A.* ; Kok, F.* ; Kotzaeridou, U.* ; Krishnamurthy, V.* ; Kučinskas, V.* ; Kuechler, A.* ; Lavillaureix, A.* ; Liu, P.* ; Manwaring, L.* ; Matsumoto, N.* ; Mazel, B.* ; McWalter, K.* ; Meiner, V.* ; Mikati, M.A.* ; Miyatake, S.* ; Mizuguchi, T.* ; Moey, L.H.* ; Mohammed, S.* ; Mor-Shaked, H.* ; Mountford, H.* ; Newbury-Ecob, R.* ; Odent, S.* ; Orec, L.* ; Osmond, M.* ; Palculict, T.B.* ; Parker, M.* ; Petersen, A.K.* ; Pfundt, R.* ; Preikšaitienė, E.* ; Radtke, K.* ; Ranza, E.* ; Rosenfeld, J.A.* ; Santiago-Sim, T.* ; Schwager, C.* ; Sinnema, M.* ; Snijders Blok, L.* ; Spillmann, R.C.* ; Stegmann, A.P.A.* ; Thiffault, I.* ; Tran, L.* ; Vaknin-Dembinsky, A.* ; Vedovato-Dos-Santos, J.H.* ; Schrier Vergano, S.A.* ; Vilain, E.* ; Vitobello, A.* ; Wagner, M. ; Waheeb, A.* ; Willing, M.* ; Zuccarelli, B.* ; Kini, U.* ; Newbury, D.F.* ; Kleefstra, T.* ; Reymond, A.* ; Fisher, S.E.* ; Vissers, L.E.L.M.*

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

Am. J. Hum. Genet. 108, 346-356 (2021)
Publ. Version/Full Text Research data DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hpo-based Analysis ; Satb1 ; Cell-based Functional Assays ; De Novo Variants ; Intellectual Disability ; Neurodevelopmental Disorders ; Seizures ; Teeth Abnormalities; Missense Mutations; Binding Protein; Expression; Interleukin-2; Chromatin; Region; Genes
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 108, Issue: 2, Pages: 346-356 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants European Union's Horizon 2020 research and innovation program
Netherlands Organization for Health Research and Development
Max Planck Society
Oxford Brookes University
Leverhulme Trust
British Academy
Swiss National Science Foundation
Lithuanian-Swiss cooperation program to reduce economic and social disparities within the enlarged European Union
Jerome Lejeune Foundation
European Commission
Aspasia grants of the Dutch Research Council