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  • Johansson, J.Uppsala University (author)

Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • SPRINGERNATURE,2024

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/327229
  • https://gup.ub.gu.se/publication/327229URI
  • https://doi.org/10.1038/s41431-023-01392-yDOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:152749556URI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-195290URI
  • https://lup.lub.lu.se/record/8b5e6a1f-fb4b-43e5-bb3f-7f4e36f54f98URI

Supplementary language notes

  • Language:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies|Uppsala University, Faculty of Medicine, for psychiatric and neurological research; Uppsala University Hospital; Svenska Laekaresaellskapet (SLS); Jeansson foundations; Swedish Society for Medical Research (SSMF); Swedish Research Council [2020-04395]; Knut and Alice Wallenberg Foundation; Saevstaholm Foundation; Uppsala University
  • RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Lideus, S.Uppsala University (author)
  • Frykholm, C.Uppsala University (author)
  • Gunnarsson, Cecilia,1970-Linköping University,Linköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Region Östergötland, Klinisk genetik,Region Östergötland, Övr Regionledningskontoret(Swepub:liu)cecgu53 (author)
  • Mihalic, F.Uppsala University (author)
  • Gudmundsson, S.Uppsala University,Broad Institute,Boston Children's Hospital (author)
  • Ekvall, S.Uppsala University (author)
  • Molin, A. M.Uppsala University (author)
  • Pham, M.Uppsala University (author)
  • Vihinen, MaunoLund University,Lunds universitet,Proteinbioinformatik,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Protein Bioinformatics,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)med-mnv (author)
  • Lagerstedt-Robinson, K.Karolinska Institute,Karolinska Institutet,Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden,Karolinska University Hospital (author)
  • Nordgren, Ann,1964Karolinska Institute,University of Gothenburg,Karolinska Institutet,Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine,Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden; Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden,Sahlgrenska University Hospital,Karolinska University Hospital(Swepub:gu)xnannb (author)
  • Jemth, P.Uppsala University (author)
  • Ameur, A. (author)
  • Anneren, G.Uppsala University (author)
  • Wilbe, M.Uppsala University (author)
  • Bondeson, M. L.Uppsala University (author)
  • Uppsala UniversityAvdelningen för diagnostik och specialistmedicin (creator_code:org_t)

Related titles

  • In:European Journal of Human Genetics: SPRINGERNATURE32:3, s. 333-3411018-48131476-5438

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