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Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions.
- Source :
-
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. - Publication Year :
- 2024
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Abstract
- 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&#95;002139.4; c.484&#95;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.<br /> (© 2023. The Author(s).)
- Subjects :
- Female
Humans
Heterogeneous-Nuclear Ribonucleoproteins genetics
Heterogeneous-Nuclear Ribonucleoproteins chemistry
Heterogeneous-Nuclear Ribonucleoproteins metabolism
RNA Polymerase II
src Homology Domains
RNA-Binding Proteins genetics
Intellectual Disability genetics
Neuroblastoma
Deafness
Optic Atrophy
Seizures
Mental Retardation, X-Linked
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5438
- Volume :
- 32
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- European journal of human genetics : EJHG
- Publication Type :
- Academic Journal
- Accession number :
- 37277488
- Full Text :
- https://doi.org/10.1038/s41431-023-01392-y