Editorial: Pseudohypoparathyroidism and mechanisms of resistance toward multiple hormones: molecular evidence to clinical presentation.

In 1942, Fuller Albright and his colleagues described a group of patients who presented with certain developmental and skeletal defects, now collectively termed Albright’s hereditary osteodystrophy (AHO), as well as biochemical abnormalities that suggested end-organ failure to respond to the actions of PTH (1). Several variants of this disorder, which was dubbed pseudohypoparathyroidism (PHP), have since been defined, and the different forms have been classified based on the absence or presence of AHO, with or without hormone resistance. The most frequently encountered variants of PHP include PHP type-Ia (PHP-Ia), pseudo-pseudohypoparathyroidism (PPHP) and PHP type-Ib (PHP-Ib). Patients with PHP-Ia have features of AHO, which typically include obesity, short stature, brachydactyly, ectopic ossification, and mental retardation, and present with hypocalcemia and hyperphosphatemia despite elevated serum PTH levels (2, 3). However, hormone resistance is usually not limited to PTH, in that affected individuals frequently show evidence also for resistance to TSH and gonadotropins (2, 3). Resistance toward other hormones, such as GHRH (4–6) and calcitonin (7, 8), has also been reported for some PHP-Ia patients, but clinical manifestations and the frequencies of these abnormalities have thus far remained poorly defined. Patients with PPHP have the typical features of AHO but do not show evidence for resistance to PTH or other hormones. In contrast, patients with PHP-Ib present with signs and symptoms of PTHresistance but lack features of AHO, and hormone resistance seems to be confined to the renal actions of PTH. Only recently, mild TSH-resistance has been observed in some PHP-Ib patients (9–11), which raises the possibility that additional endocrine systems may also be affected in this variant of PHP. The molecular defects responsible for these three main forms of PHP appear to reside in GNAS, the gene encoding the -subunit of the stimulatory GTP binding protein (Gs ) and other recently identified transcripts. Patients with PHP-Ia have heterozygous mutations in one of the 13 exons encoding Gs (12), leading to reduced Gs protein level and cellular activity, as shown in erythrocytes and other easily accessible cells (2, 3). These mutations explain that all hormones whose actions are impaired in PHP-Ia act via receptors that couple to Gs . Interestingly, Gs mutations are also present in patients with PPHP, who do not present with hormone resistance although they have typical AHO features. Furthermore, PHP-Ia and PPHP are frequently found in the same kindred, and the development of one disorder or the other depends on the gender of the parent transmitting the genetic defect (13, 14). Inheritance of the molecular defect from a male affected by either PHP-Ia or PPHP leads to PPHP, i.e. AHO without hormone resistance, while inheritance of the same Gs mutation from a female affected by either disorder leads to PHP-Ia, i.e. both AHO and hormone resistance. Thus, the identified Gs mutations are necessary but not sufficient for the phenotypic expression of these two disorders. The genetic mutation leading to an autosomal dominant form of PHP-Ib appears to be an approximately 3-kb deletion more than approximately 200-kb upstream of GNAS (15). Similar to PHP-Ia, this form of PHP-Ib develops only if the genetic defect is transmitted from a female carrier. It is postulated that the approximately 3-kb deletion leads, through yet unknown mechanisms, to a loss-of-methylation defect in GNAS, thereby impairing transcription of Gs mRNA in a tissue-specific manner. Gs is a ubiquitously expressed signaling protein, which mediates cellular actions of numerous hormones, paracrine/ autocrine factors, and neurotransmitters (16). In PHP-Ia, however, only a limited number of hormones that rely on Gs signaling appear to be affected. For example, cellular responses to isoproterenol, glucagon, and vasopressin, all of which mediate their actions through Gs -coupled receptors, are seemingly intact (17–19). This selective nature of hormone resistance in PHP-Ia, and the parent-of-origin specific mode of inheritance in PHP-Ia/PPHP kindreds suggest that Gs mRNA is transcribed in certain hormone-responsive cells only from one parental allele. Consequently, heterozygous Gs mutations can lead to hormone resistance only in those tissues or cells in which monoallelic Gs expression occurs. In other tissues, the approximately 50% decrease in the Gs level is expected to cause a reduction in cAMP formation, but the cAMP levels generated can sufficiently maintain all physiological responses, i.e. there is currently no evidence for haploinsufficiency. However, earlier studies using RNA preparations from whole organs, but not from single cells, could only demonstrate biallelic expression of Gs (20–23), and it has therefore remained unclear whether monoallelic Gs expression plays a role in hormone responsiveness in PHP-Ia (or PHP-Ib). Detailed investigations of GNAS have recently provided new insights into Gs expression and the mechanisms underlying hormone resistance. We now know that, besides Gs , GNAS gives rise to several other transcriptional units derived from the sense or antisense strand. Transcripts encoding XL s, a large variant of Gs , show exclusive paternal expression and are derived through the use of an alternative promoter and a unique first exon, which splices onto exons Abbreviations: AHO, Albright’s hereditary osteodystrophy; Gs , GTP binding protein; PHP, pseudohypoparathyroidism; PHP-Ia, PHP type-Ia; PHP-Ib, PHP type-Ib; PPHP, pseudo-pseudohypoparathyroidism. 0021-972X/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(9):4055–4058 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2003-031271