| Theme |
Genome analysis in the field of bone metabolism |
| Title |
Regulation of GNAS1 gene expression and the associated disorders |
| Author |
Masanori Kanatani |
Division of Endocrinology / Metabolism, Neurology and Hematology / Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine |
| Author |
Toshitsugu Sugimoto |
Division of Endocrinology / Metabolism, Neurology and Hematology / Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine |
| [ Summary ] |
The heterotrimeric G proteins Gs couples hormone receptors to the effector enzyme, adenylyl cyclase and is required for hormone action. Mutations of specific Gs alpha residues that lead to constitutive activation of Gs-coupled signaling pathways are found in 40% of human pituitary GH-secreting tumors and McCune Albright syndrome. Conversely, heterozygous loss-of-function mutations lead to Albright hereditary osteodystrophy. Gs alpha is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule). Thus, disrupting mutations in the maternal allele lead to loss of PTH action in the kidney (PHP Ia), while mutations in the paternal allele have little effect on PTH action (PPHP). The gene responsible for PHP Ib is imprinted paternally and thus is inherited in the same mode as PHP Ia. In patients with PHP Ib, the exon A/B promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated), suggesting that the GNAS1 imprinting defect is predicted to decrease Gs alpha expression in renal proximal tubules. |