Variable and tissue-specific hormone resistance in heterotrimeric G s protein α-subunit (G s α) knockout mice is due to tissue-specific imprinting of the G s α gene

Albright hereditary osteodystrophy (AHO), an autosomal dominant disorder characterized by short stature, obesity, and skeletal defects, is associated with heterozygous inactivating mutations ofGNAS1 , the gene encoding the heterotrimeric G protein α-subunit (Gs α) that couples multiple receptors to the stimulation of adenylyl cyclase. It has remained unclear why only some AHO patients present with multihormone resistance and why AHO patients demonstrate resistance to some hormones [e.g., parathyroid hormone (PTH)] but not to others (e.g., vasopressin), even though all activate adenylyl cyclase. We generated mice with a null allele of the mouse homologGnas. Homozygous Gs deficiency is embryonically lethal. Heterozygotes with maternal (m−/+) and paternal (+/p−) inheritance of theGnas null allele have distinct phenotypes, suggesting thatGnas is an imprinted gene. PTH resistance is present in m−/+, but not +/p−, mice. Gs α expression in the renal cortex (the site of PTH action) is markedly reduced in m−/+ but not in +/p− mice, demonstrating that theGnas paternal allele is imprinted in this tissue.Gnas is also imprinted in brown and white adipose tissue. The maximal physiological response to vasopressin (urinary concentrating ability) is normal in both m−/+ and +/p− mice andGnas is not imprinted in the renal inner medulla (the site of vasopressin action). Tissue-specific imprinting ofGnas is likely the mechanism for variable and tissue-specific hormone resistance in these mice and a similar mechanism might explain the variable phenotype in AHO.