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  SETBP1 variants outside the degron disrupt DNA-binding and transcription independent of protein abundance to cause a heterogeneous neurodevelopmental disorder

Wong, M. M. K., Kampen, R. A., Braden, R. O., Alagöz, G., Hildebrand, M. S., Barnett, C., et al. (2022). SETBP1 variants outside the degron disrupt DNA-binding and transcription independent of protein abundance to cause a heterogeneous neurodevelopmental disorder. medRxiv, 10.1101/2022.03.04.22271462. doi:10.1101/2022.03.04.22271462.

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Wong_etal_2022_preprint.pdf (Preprint), 549KB
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Wong_etal_2022_preprint.pdf
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Copyright Datum:
2022
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The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license

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 Urheber:
Wong, Maggie M. K.1, Autor           
Kampen, Rosalie A., Autor
Braden, Ruth O., Autor
Alagöz, Gökberk1, Autor           
Hildebrand, Michael S., Autor
Barnett, Christopher, Autor
Barnett, Meghan, Autor
Brusco, Alfredo, Autor
Carli, Diana, Autor
De Vries, Bert B. A., Autor
Dingemans, Alexander J. M., Autor
Elmslie, Frances, Autor
Ferrero, Giovanni B., Autor
Jansen, Nadieh A., Autor
Van de Laar, Ingrid M. B. H., Autor
Moroni, Alice, Autor
Mowat, David, Autor
Murray, Lucinda, Autor
Novara, Francesca, Autor
Peron, Angela, Autor
Scheffer, Ingrid E, AutorSirchia, Fabio, AutorTurner, Samantha J., AutorVignoli, Aglaia, AutorVino, Arianna1, Autor           Weber, Sacha, AutorChung, Wendy K, AutorGerard, Marion, AutorLópez-González, Vanessa, AutorPalmer, Elizabeth, AutorMorgan, Angela T., AutorVan Bon, Bregje W., AutorFisher, Simon E.1, Autor            mehr..
Affiliations:
1Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society, ou_792549              

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 Zusammenfassung: Germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders. Heterozygous missense variants at a hotspot encoding a canonical degron lead to SETBP1 accumulation and Schinzel-Giedion syndrome (SGS), a rare severe developmental disorder involving multisystem malformations. Heterozygous loss-of-function variants result in SETBP1 haploinsufficiency disorder which is phenotypically much milder than SGS. Following an initial description of four individuals with atypical SGS carrying heterozygous missense variants adjacent to the degron, a few individual cases of variants outside the degron were reported. Due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of the roles of the gene in brain development, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive, imposing challenges for diagnosis and patient care. Here, we present a comprehensive investigation of the largest cohort to-date of individuals carrying SETBP1 missense variants outside the degron (n=18, including one in-frame deletion). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1 haploinsufficiency disorder, and primarily characterised by intellectual disability, epilepsy, speech and motor impairment. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding and transcription. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care and aetiology of SETBP1-related disorders.

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Sprache(n): eng - English
 Datum: 2022-03-08
 Publikationsstatus: Online veröffentlicht
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 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Keine Begutachtung
 Identifikatoren: DOI: 10.1101/2022.03.04.22271462
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Titel: medRxiv
Genre der Quelle: Zeitschrift
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Seiten: - Band / Heft: - Artikelnummer: 10.1101/2022.03.04.22271462 Start- / Endseite: - Identifikator: -