A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms

K E Ahlers-Dannen; J Yang; M M Spicer; D Fu; A DeVore; R A Fisher

doi:10.1038/s10038-024-01220-1

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A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms

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A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms

K E Ahlers-Dannen, J Yang, M M Spicer, D Fu, A DeVore and R A Fisher

Journal of human genetics, Vol.69(3-4), pp.145-152

04/2024

DOI: 10.1038/s10038-024-01220-1

PMCID: PMC11485174

PMID: 38332109

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https://pmc.ncbi.nlm.nih.gov/articles/PMC11485174/pdf/nihms-2020325.pdfView

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Abstract

Intellectual disability (ID) is associated with an increased risk of developing psychiatric disorders, suggesting a common underlying genetic factor. Importantly, altered signaling and/or expression of regulator of G protein signaling 6 (RGS6) is associated with ID and numerous psychiatric disorders. RGS6 is highly conserved and undergoes complex alternative mRNA splicing producing ~36 protein isoforms with high sequence similarity historically necessitating a global approach in functional studies. However, our recent analysis in mice revealed RGS6 is most highly expressed in CNS with RGS6L(+GGL) isoforms predominating. A previously reported genetic variant in intron 17 of RGS6 (c.1369-1G>C), associated with ID, may provide further clues into RGS6L(+GGL) isoform functional delineation. This variant was predicted to alter a highly conserved canonical 3' acceptor site creating an alternative branch point within exon 18 (included in a subset of RGS6L(+GGL) transcripts) and a frameshift forming an early stop codon. We previously identified this alternative splice site and demonstrated its use generates RGS6Lζ(+GGL) isoforms. Here, we show that the c.1369-1G>C variant disrupts the canonical, preferred (>90%) intron 17 splice site and leads to the exclusive use of the alternate exon 18 splice site, inducing disproportionate expression of a subset of isoforms, particularly RGS6Lζ(+GGL). Furthermore, RGS6 global knockout mice do not exhibit ID. Thus, ID caused by the c.1369-1G>C variant likely results from altered RGS6 isoform expression, rather than RGS6 isoform loss. In summary, these studies highlight the importance of proper RGS6 splicing and identify a previously unrecognized role of G protein signaling in ID.

Details

Title: Subtitle: A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms
Creators: K E Ahlers-Dannen - University of Iowa
J Yang - University of Iowa
M M Spicer - University of Iowa
D Fu - University of Iowa
A DeVore - University of Iowa
R A Fisher - Department of Neuroscience and Pharmacology, The Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. rory-fisher@uiowa.edu
Resource Type: Journal article
Publication Details: Journal of human genetics, Vol.69(3-4), pp.145-152
DOI: 10.1038/s10038-024-01220-1
PMID: 38332109
PMCID: PMC11485174
NLM abbreviation: J Hum Genet
eISSN: 1435-232X
Grant note: AA025919-03S1 / U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) AA025919-05S1 / U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)
Language: English
Electronic publication date: 02/09/2024
Date published: 04/2024
Academic Unit: Neurology; Psychiatry; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984557944302771

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