In PHP type 1, cyclic AMP is not synthesized in response to PTH, because of a deficiency of the coupling protein Gα_s. As a result, little cyclic AMP is produced in target tissues in response to PTH, and functional hypoparathyroidism develops (see Plate 3-5). This defect can be demonstrated in patients by measuring the level of cyclic AMP in urine after an injection of PTH. In normal persons and in patients with hypoparathyroidism, the rise in the excretion of cyclic AMP in urine is rapid and marked; in patients with PHP type 1, it is blunted or absent (see Plate 3-10).

The gene encoding Gα_s, GNAS, is a very complex transcriptional unit that derives considerable plasticity through use of alternative first exons, alternative splicing of downstream exons, antisense transcripts, and reciprocal imprinting. Four alternative exons, NESP55, XLαs, exon A/B, and exon 1, splice onto exons 2 to 13 of GNAS. Transcripts originating from alternative exons A/B and XLαs are expressed exclusively from the paternal allele. Exon A/B transcripts are probably nontranslated. By contrast, the XLαs protein shares C-terminal sequences with Gα_s and functions in G-protein–coupled signal transduction. Transcripts starting with exon 1 encode Gα_s and are expressed from both the maternal and paternal alleles in most tissues. Loss of one functional GNAS allele (i.e., haploinsufficiency) does not cause hormone resistance in these tissues, because 50% of normal Gα_s activity is sufficient to ensure normal transmembrane signal transduction. By contrast, suppression of the paternal allele occurs in cells such as renal proximal tubule cells, thyroid follicular cells, pituitary somatotrophs, and the paraventricular nucleus of the hypothalamus. Hence, mutations of the maternal GNAS allele results in expression of little if any Gα_s protein in these imprinted tissues and is associated with hormone resistance. Thus, variable hormone resistance, from tissue to tissue between patients, reflects an unusual set of requirements that specifies that the tissue must exhibit imprinting of Gα_s transcripts and the mutation must be on the maternal GNAS allele. By contrast, when the same GNAS mutation is carried on the paternal allele hormone, responsiveness is normal. Subjects with paternally inherited GNAS mutations have phenotypical features of AHO without hormonal resistance, a condition termed pseudopseudohypoparathyroidism (pseudoPHP). Subjects with pseudoPHP have a normal urinary cyclic AMP response to PTH, which distinguishes them from occasional patients with PHP type 1a who maintain normal serum calcium levels without treatment. It is not unusual to find extended families in which some members will have only AHO (pseudoPHP) whereas others will have hormone resistance as well (PHP type 1a), based on the parental origin of the identical GNAS mutation.