AHO features are present in both PHP-Ia and PPHP patients, and therefore, the molecular mechanisms underlying AHO presumably entail Gsα haploinsufficiency rather than imprinting. Gsα haploinsufficiency has been demonstrated in the growth plate of mice chimeric for wild-type cells and cells heterozygous for disruption of either the maternal or the paternal Gnas exon 2 [143]. In the chimeric setting, the mutant chondrocytes undergo hypertrophic differentiation sooner than wild-type chondrocytes, and because this finding is qualitatively similar to (albeit far less severe than) that observed in chondrocytes with homozygous Gsα ablation under the same conditions, it indicates Gsα haploinsufficiency. While this study strongly suggests that the short stature and the brachydactyly seen in patients with AHO reflect, at least in part, Gsα haploinsufficiency in the growth plate, some features of AHO may still involve Gsα imprinting in the pathogenesis. For example, a recent study has clearly shown that obesity is more prominent in PHP-Ia patients than PPHP patients [144]. Thus, it appears that Gsα may be imprinted in more tissues than currently recognized, such as in parts of the brain that
