Before the evidence that several different GNAS transcripts, in addition to Gsα, utilize exon 2, a mouse model of PHP-Ia was generated by targeted disruption of this exon [40]. Homozygous disruption of exon 2 results in early embryonic lethality. Furthermore, paternal heterozygous disruption leads to lethality within the first 24 h after birth, and maternal heterozygous disruption results in death within the first three weeks. Surviving animals are fertile and appear to have normal life spans. As explained above, mice with paternal disruption of Gnas exon 2 have severe defects that are similar to those seen in mice with paternal disruption of Gnasxl [67], including reduced adiposity, which is not seen in patients with paternally inherited inactivating Gsα mutations (PPHP); these patients are typically overweight. On the other hand, both the maternal and the paternal Gnas exon 2 knockout mice appear smaller than their littermates, reminiscent of the short stature observed in patients with AHO. Furthermore, the exon 2 knockout mice prove to be a good model of PTH resistance. Reflecting the tissue-specific silencing of paternal Gsα in the proximal
