Imprinting and skeletal disorders: lessons from pseudohypoparathyroidism and related disorders

Pseudohypoparathyroidism (PHP) was first described as a syndrome characterized by PTH resistance combined with skeletal abnormalities known as Albright's hereditary osteodystrophy (AHO). Studies have since focused on genetic or epigenetic alterations underlying PHP and related disorders. The α-subunit of the stimulatory G protein (Gsα) mediates the signaling of G protein-coupled receptors that stimulate cAMP generation. The Gsα-cAMP cascade is pivotal for human skeletal growth, as evidenced by pathogenic mutations converging on this signaling pathway in a spectrum of skeletal dysplasias that overlap with AHO. The gene encoding Gsα, GNAS, is subject to genomic imprinting, an epigenetic mechanism governing allele-specific gene expression through differential methylation. Parental allele contribution to Gsα expression differs among tissues. While Gsα is biallelically transcribed in most tissues, including bone and cartilage, the paternal Gsα allele is suppressed in a limited number of cells/tissues, including the proximal renal tubule, where PTH exerts critical actions. Therefore, Gsα mutations cause distinct clinical manifestations according to the affected parental allele. While maternal mutations result in PHP type 1A, which consists of PTH resistance and AHO, paternal mutations lead to pseudo-pseudohypoparathyroidism (PPHP), that is, AHO without hormone resistance. Epigenetic alterations of GNAS cause PHP type 1B (PHP1B), defined by PTH resistance in the absence of AHO. Thus, genomic imprinting plays a key role in the phenotypes associated with GNAS alterations. Investigations on the genetic cause of PHP1B have identified crucial imprinting control regions of GNAS, whose functions were elucidated only recently using human embryonic stem cells to model imprinting regulatory mechanisms in the early embryo. We herein review the current understanding of the genetic and epigenetic basis of PHP and related disorders, focusing on their skeletal manifestations.