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

Den Hoed, J., De Boer, E., Voisin, N., Dingemans, A. J. M., Guex, N., Wiel, L., et al. (2021). Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. The American Journal of Human Genetics, 108(2), 346-356. doi:10.1016/j.ajhg.2021.01.007.

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2021
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open archive Elsevier
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Den Hoed, Joery1, 2, Autor           
De Boer, E3, 4, Autor
Voisin, N.5, Autor
Dingemans, A. J. M.3, 4, Autor
Guex, N.5, Autor
Wiel, L.3, Autor
Nellaker, C.6, Autor
Amudhavalli, S. M.7, 8, Autor
Banka, S.9, Autor
Bena, F. S.10, Autor
Ben-Zeev, B.11, Autor
Bonagura, V. R.12, 13, Autor
Bruel, A.-L.14, 15, Autor
Brunet, T., Autor
Brunner, H. G., Autor
Chew, H. B., Autor
Chrast, J., Autor
Cimbalistienė, L., Autor
Coon, H., Autor
The DDD study, Autor              
Délot, E. C., AutorDémurger, F., AutorDenommé-Pichon, A.-S. , AutorDepienne, C., AutorDonnai, D., AutorDyment, D. A., AutorElpeleg, O., AutorFaivre, L., AutorGilissen, C., AutorGranger, L., AutorHaber, B., AutorHachiya, Y., AutorHamzavi Abedi, Y. , AutorHanebeck, J., AutorHehir-Kwa, J. Y., AutorHorist, B., AutorItai, T., AutorJackson, A., AutorJewell, R., AutorJones, K. L., AutorJoss, S., AutorKashii, H., AutorKato, M., AutorKattentidt-Mouravieva, A. A., AutorKok, F., AutorKotzaeridou, U., AutorKrishnamurthy, V., AutorKučinskas, V., AutorKuechler, A., AutorLavillaureix, A., AutorLiu, P., AutorManwaring, L., AutorMatsumoto, N., AutorMazel, B., AutorMcWalter, K., AutorMeiner, V., AutorMikati, M. A., AutorMiyatake, S., AutorMizuguchi, T., AutorMoey, L. H., AutorMohammed, S., AutorMor-Shaked, H., AutorMountford, H., AutorNewbury-Ecob, R. , AutorOdent, S., AutorOrec, L., AutorOsmond, M., AutorPalculict, T. B., AutorParker, M., AutorPetersen, A., AutorPfundt, R., AutorPreikšaitienė, E., AutorRadtke, K., AutorRanza, E., AutorRosenfeld, J. A., AutorSantiago-Sim, T., AutorSchwager, C., AutorSinnema, M., AutorSnijders Blok, Lot1, Autor           Spillmann, R. C., AutorStegmann, A. P. A., AutorThiffault, I., AutorTran, L., AutorVaknin-Dembinsky, A., AutorVedovato-dos-Santos, J. H., AutorVergano, S. A., AutorVilain, E., AutorVitobello, A., AutorWagner, M., AutorWaheeb, A., AutorWilling, M., AutorZuccarelli, B., AutorKini, U., AutorNewbury, D. F., AutorKleefstra, T., AutorReymond, A., AutorFisher, Simon E.1, Autor           Vissers, L. E. L. M., Autor mehr..
Affiliations:
1Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society, ou_792549              
2International Max Planck Research School for Language Sciences, MPI for Psycholinguistics, Max Planck Society, Nijmegen, NL, ou_1119545              
3Radboud University Medical Center, Nijmegen, The Netherlands, ou_persistent22              
4Donders Institute for Brain, Cognition and Behaviour, External Organizations, ou_55236              
5University of Lausanne, Lausanne, Switzerland, ou_persistent22              
6University of Oxford, Oxford, UK, ou_persistent22              
7University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA, ou_persistent22              
8Children’s Mercy Hospital, Kansas City, MO, USA, ou_persistent22              
9Manchester University, Manchester, UK, ou_persistent22              
10University Hospitals of Geneva, Geneva, Switzerland, ou_persistent22              
11Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel, ou_persistent22              
12Feinstein Institutes for Medical Research, Manhasset, NY, USA , ou_persistent22              
13Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA, ou_persistent22              
14Université Bourgogne Franche-Comté , Dijon, France, ou_persistent22              
15Centre Hospitalier Universitaire de Dijon, Dijon, France, ou_persistent22              

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 Zusammenfassung: 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. Contrastingly, 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 and encode truncated proteins, 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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Sprache(n): eng - English
 Datum: 2021-01-282021
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1016/j.ajhg.2021.01.007
 Art des Abschluß: -

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Titel: The American Journal of Human Genetics
  Andere : Am. J. Hum. Genet.
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: American Society of Human Genetics
Seiten: - Band / Heft: 108 (2) Artikelnummer: - Start- / Endseite: 346 - 356 Identifikator: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1