Consistent with the pivotal role of Gsα in multiple biological responses, mutations that affect the activity or expression of Gsα lead to human disease. However, there are no disorders caused by inactivation of both Gsα alleles, i.e. homozygous inactivating Gsα mutations, and this is consistent with the early embryonic lethality observed in mice with homozygous disruption of either Gnas exon 2 or Gnas exon 1 [40, 41, 82]. Thus, complete loss of Gsα activity is not compatible with life. Moreover, there are mutations that cause constitutive Gsα activity, but these are virtually never inherited and are of somatic origin, indicating that universal Gsα overactivity is embryonic lethal, as well.
