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

Autor: Johansson J; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Lidéus S; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Frykholm C; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Gunnarsson C; Department of Clinical Genetics, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Centre for Rare Diseases in South East Region of Sweden, Linköping University, Linköping, Sweden., Mihalic F; Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, 751 23, Uppsala, Sweden., Gudmundsson S; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Ekvall S; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Molin AM; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Pham M; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Vihinen M; Department of Experimental Medical Science, BMC B13, Lund University, SE-22 184, Lund, Sweden., Lagerstedt-Robinson K; Clinical Genetics, Karolinska University Hospital, Solna, Sweden.; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Nordgren A; Clinical Genetics, Karolinska University Hospital, Solna, Sweden.; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.; Institute of Biomedicine, Department of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden., Jemth P; Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, Husargatan 3, 751 23, Uppsala, Sweden., Ameur A; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Annerén G; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Wilbe M; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden., Bondeson ML; Department of Immunology, Genetics and Pathology, Biomedical Centre, Uppsala University, Uppsala, Sweden. marielouise.bondeson@igp.uu.se.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Mar; Vol. 32 (3), pp. 333-341. Date of Electronic Publication: 2023 Jun 05.
DOI: 10.1038/s41431-023-01392-y
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE