Lack of heterotrimeric G protein beta 5 impairs brain development and neurologic function in mice

Gβ5 is a member of the heterotrimeric G protein β subunit family that is expressed principally in brain and neuronal tissues. Previous studies employing Gβ5 knockout mice have shown that Gβ5 is an essential stabilizer of GGL domain‐containing RGS proteins and regulates the deactivation of retinal phototransduction. This study is focused on the functions of Gβ5 in the brain outside the visual system using molecular biology, immunohistochemistry and confocal imaging technologies. We show here that mice lacking Gβ5 have a markedly abnormal neurologic phenotype that includes neurobehavioral developmental delay, wide‐based gait, motor learning and coordination deficiencies, and hyperactivity. The neurobehavioral phenotype is likely caused in part by the delayed development of the cerebellar cortex. Multiple neuronally‐expressed genes are dysregulated in Gβ5 KO mice. The marked developmental delay observed in Gβ5‐deficient mice would, in humans, almost certainly be accompanied by intellectual disability. We therefore propose GNB5 on human chromosome 15 as a candidate gene for a subset of autosomal recessive mental retardation, a devastating and heterogeneous disorder with mostly unknown etiologies, that is a major cause of early onset cognitive impairment. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.