Journal Article


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

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.

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Authors

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.
Pfundt, R.
Preikšaitienė, E.
Radtke, K.
Ranza, E.
Rosenfeld, J.A.
Santiago-Sim, T.
Schwager, C.
Sinnema, M.
Blok, L.S.
Spillmann, R.C.
Stegmann, A.P.A.
Thiffault, I.
Tran, L.
Vaknin-Dembinsky, A.
Vedovato-dos-Santos, J.H.
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.

Oxford Brookes departments

Department of Biological and Medical Sciences

Dates

Year of publication: Not yet published.
Date of RADAR deposit: 2021-01-15


Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License


Related resources

This RADAR resource is the Accepted Manuscript of Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
This RADAR resource is the Accepted Manuscript of [preprint] Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

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  • Owner: Joseph Ripp
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