Albright hereditary osteodystrophy: Current progress and new frontiers

Abstract

Albright hereditary osteodystrophy (AHO) is a rare genetic disorder characterized by phenotypic abnormalities including brachydactyly , brachymetacarpia, short stature , subcutaneous ossifications , and dental abnormalities. This disorder is caused by heterozygous, inactivating mutations in GNAS , the gene encoding the alpha chain of the heterotrimeric G protein, Gs, that couples with receptors for many hormones and neurotransmitters for the activation of adenylyl cyclase. Transcripts encoding Gαs are preferentially expressed from the maternally inherited allele in the renal proximal tubule, thyroid, gonad, and pituitary. AHO patients who have GNAS mutations on maternally inherited alleles manifest resistance to multiple hormones (including PTH, TSH, gonadotropins, and GHRH) as well as obesity and cognitive deficits. This condition is termed pseudohypoparathyroidism type Ia (PHP Ia) and is due to tissue-specific paternal imprinting. Conversely, patients with AHO and GNAS mutations on their paternally inherited alleles have no evidence of hormonal resistance, are typically not obese, and cognitive function may be normal. This condition is termed pseudopseudohypoparathyroidism (PPHP). Current knowledge as well as the research in progress in both humans and mouse models regarding the major clinical problems in AHO will be reviewed. Dr. Germain-Lee will focus on her past and current research involving clinical trials with growth hormone in patients with AHO, as well as her research on the heterotopic ossifications that develop in this condition, which she is examining through the use of a mouse model. Her research on the etiology and mechanisms underlying the formation of the heterotopic ossifications has broader implications in terms of the potential to understand more about the mechanisms of osteogenesis overall. In addition, Dr. Germain-Lee will discuss her clinical findings related to the severe obesity in pseudohypoparathyroidism type Ia; this severe obesity is not present in pseudopseudohypoparathyroidism. Dr. Weinstein will discuss his basic science research on metabolism and obesity in AHO, which is based on his studies of his mouse models of this condition. In addition, he will discuss his current ongoing clinical studies of obesity and metabolism in AHO.