Chen et al. [82] and Germain-Lee et al. [41] have independently generated another model of PHP-Ia through targeted disruption of Gnas exon 1. In addition to early embryonic lethality observed upon homozygous inheritance of exon 1 disruption, even the heterozygous disruption is associated with some pre-weaning mortality regardless of the parental origin. While this finding is not observed in families with PHP-Ia/PPHP, the overall phenotype of mice heterozygous for maternal disruption of Gnas exon 1 resembles that of PHP-Ia remarkably. Mice with maternal disruption of exon 1 develop biochemical features consistent with PTH resistance [41]. In humans with inactivating Gsα mutations it is accepted that obesity develops regardless of the parent-of-origin of the introduced mutation, but recent evidence indicates that patients with PHP-Ia exhibit more prominent obesity than patients with PPHP [144]. Consistent with this recent observation, mice with the maternal Gnas exon 1 disruption is more obese than the paternal disruption [82]. In contrast to these similarities between the mouse models of exon 1 ablation and PHP-Ia/PPHP, the serum PTH level seems to be moderately elevated in mice with
