Molecular Definition of Pseudohypoparathyroidism

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DESCRIPTION (provided by applicant): Patients affected by pseudohypoparathyroidism type Ib (PHP-Ib) display variable degrees of hypocalcemia and hyperphosphatemia due to PTH-resistance. These individuals show, however, no evidence for Albright's hereditary osteodystrophy (AHO) and are thus distinct from patients with pseudohypoparathyroidism type Ia (PHP-Ia) and pseudo-pseudohypoparathyroidism (pPHP). Because of the selective resistance to a single hormone, PTH, PHP-Ib was initially thought to be caused by mutations in the PTH-receptor, now referred to as the PTH/PTHrP receptor. However, our laboratory and other groups excluded such mutations. More importantly, PTH/PTHrP receptor mutations, either activating or inactivating, are now known to lead to severe abnormalities in the regulation of mineral ion homeostasis and bone development, which is different from the often very mild laboratory abnormalities observed in PHP-Ib patients. This suggested that the genetic defect lies in a yet unknown gene with a prominent role in regulating the expression of the PTH/PTHrP receptor and/or down-stream signaling proteins. A genome-wide scan was therefore conducted and revealed linkage of the autosomal dominant form of PHP-Ib to chromosome 20q 13.3, which comprises GNAS1 at its telomeric boundary. These studies furthermore showed that the disease is paternally imprinted, i.e. hormonal resistance is only transmitted to the next generation if the disease-associated allele is inherited from an obligate female carrier. This mode of inheritance is similar to the findings in kindreds with PHP-Ia/pPHP, two related disorders that are caused by heterozygous, inactivating mutations in one of the thirteen GNAS1 exons encoding Gs-alpha. Besides encoding the ubiquitous signaling protein, GNAS1 gives rise to at least four additional coding and non-coding/non-translated transcripts, and the promoter region for several of these transcripts undergoes parent-specific methylation and thus inactivation. One of these epigenetic changes, i.e. a loss of methylation at the A/B exon (also referred to exon 1A or 1'), has thus far been shown to occur specifically in patients affected by PHP-Ib. However, the genetic mutation leading to this methylation abnormality and presumably to PTH-resistance appears to be located at least 50 kb up-stream of the epigenetic defect, most likely in an intronic regulatory region. We now propose to identify this genetic mutation(s) through nucleotide sequence analysis, additional linkage studies, or an in vivo approach with transgenic animals, and to explore the molecular mechanism(s) underlying PTH-resistance in the renal cortex.