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.

Attached files

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

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

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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