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

Johansson, Josefin ; Lidéus, Sarah ; Frykholm, Carina ; Gunnarsson, Cecilia ; Mihalic, Filip ; Gudmundsson, Sanna ; Ekvall, Sara ; Molin, Anna Maja ; Pham, Mai and Vihinen, Mauno LU orcid , et al. (2023) In European Journal of Human Genetics
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... (More)

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.

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in press
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European Journal of Human Genetics
publisher
Nature Publishing Group
external identifiers
  • pmid:37277488
  • scopus:85160863898
ISSN
1018-4813
DOI
10.1038/s41431-023-01392-y
language
English
LU publication?
yes
id
8b5e6a1f-fb4b-43e5-bb3f-7f4e36f54f98
date added to LUP
2023-09-15 11:43:51
date last changed
2024-04-20 03:26:07
@article{8b5e6a1f-fb4b-43e5-bb3f-7f4e36f54f98,
  abstract     = {{<p>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.</p>}},
  author       = {{Johansson, Josefin and Lidéus, Sarah and Frykholm, Carina and Gunnarsson, Cecilia and Mihalic, Filip and Gudmundsson, Sanna and Ekvall, Sara and Molin, Anna Maja and Pham, Mai and Vihinen, Mauno and Lagerstedt-Robinson, Kristina and Nordgren, Ann and Jemth, Per and Ameur, Adam and Annerén, Göran and Wilbe, Maria and Bondeson, Marie Louise}},
  issn         = {{1018-4813}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{European Journal of Human Genetics}},
  title        = {{Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions}},
  url          = {{http://dx.doi.org/10.1038/s41431-023-01392-y}},
  doi          = {{10.1038/s41431-023-01392-y}},
  year         = {{2023}},
}