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.
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Acknowledgements
The work presented in this manuscript was supported by NIH AA025919-03S1 and AA025919-05S1.
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Conceptualization: K.E.A-D., J.Y., M.M.S., R.F.; Formal Analysis: K.E.A-D., J.Y., M.M.S.; Funding Acquisition: R.F.; Investigation: K.E.A-D., J.Y., M.M.S., D.F., A.D.; Methodology: K.E.A-D., J.Y., M.M.S., A.D., R.F.; Project Administration: K.E.A-D., J.Y., R.F.; Visualization: K.E.A-D., J.Y., M.M.S., A.D.; Writing-original Draft: K.E.A-D., J.Y., M.M.S, D.F., A.D., R.F.; Writing-review & Editing: K.E.A-D., J.Y., M.M.S, D.F., A.D., R.F.
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All animal procedures described here were approved by the University of Iowa Institute for Animal Care and Use Committee.
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Ahlers-Dannen, K.E., Yang, J., Spicer, M.M. et al. A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms. J Hum Genet 69, 145–152 (2024). https://doi.org/10.1038/s10038-024-01220-1
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DOI: https://doi.org/10.1038/s10038-024-01220-1