Abstract
Heterozygous loss-of-function GNAL mutations are one established cause of isolated dystonia and hyposmia. Homozygous GNAL mutations have been reported in siblings with generalized dystonia and intellectual disability. GNAL encodes major [NM_001369387.1; Gα(olf)] and long [NM_182978.4; XLGα(olf)] isoforms. In striatal medium spiny neurons, dopamine D1 receptors and adenosine A2a receptors are coupled to adenylyl-cyclase through a heterotrimeric G-protein complex composed of Gα(olf), Gβ2, and Gγ7 subunits. In the cerebellum, Gα(olf) colocalizes with cell-surface corticotropin-releasing factor receptors (CRF-RI/II) which take part in climbing fiber signaling. In contrast, XLGα(olf) may take part in cell-cycle control and development. In situ hybridization (ISH) showed that XLGα(olf) mRNA was more broadly distributed in mouse brain than Gα(olf) mRNA. In the cerebellum, XLGα(olf) mRNA was seen in all layers of cerebellar cortex while Gα(olf) mRNA was mainly limited to Purkinje cells. Gα(olf) showed higher expression than XLGα(olf) in the olfactory bulb and striatum, and lower expression than XLGα(olf) in cerebral cortex, cerebellar cortex, and hippocampus. Dysregulated genes identified in Gnal (+/-) mouse brain contribute to signaling (Slc5a7, Cbln2, Glra3, Rtn4rl2), anatomical structure development including dendritogenesis (Slc5a7, Cbln2, Glra3, Rtn4rl2, XLr3b, Mmp12, Rtn4rl2, Cd74, Kirrel2), and DNA-templated transcription (Lhx9, Basp1, Mmp12, Cd74). Analyses of ClinVar and gnomAD databases suggest that highly deleterious GNAL variants isolated to Exon 1 of the long isoform are less likely to be pathogenic than those isolated to Exon 1 of the major isoform. This work forms a platform for continued study of Gα(olf) and XLGα(olf) in dystonia, hyposmia, and intellectual disability.