Pseudohypoparathyroidism (PHP) is a disorder of hormone resistance characterized by end-organ resistance to the actions of parathyroid hormone (PTH). The resistance primarily occurs in the renal proximal tubule, thus leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. Indicating the resistance in this tissue, patients with PHP show blunted phosphate excretion in response to exogenously administered PTH. In PHP type I, the patients additionally demonstrate blunted PTH-induced urinary cAMP excretion. Patients with PHP-Ia demonstrate resistance to additional hormones, including TSH and gonadotropins. Moreover, these patients present with Albrights hereditary osteodystrophy (AHO). PHP-Ia is caused by heterozygous inactivating mutations in GNAS, the gene encoding the alpha-subunit of the stimulatory G protein (Gsα). These mutations, which are located in Gsα-coding GNAS exons, cause PHP-Ia after maternal inheritance but lead to pseudo-pseudohypoparathyroidism (PPHP) after paternal inheritance. PPHP is a disorder characterized by AHO in the absence of hormone resistance. Reflecting the inactivating nature of the Gsα mutations, biochemical assays using easily accessible cells of PHP-Ia and PPHP patients show ~50% reduction in Gsα bioactivity. Another form of PHP type I is PHP-Ib, which is typically characterized by the presence of PTH and mild TSH resistance in the absence of AHO. Hormone resistance in PHP-Ib is also inherited from female obligate carriers only. Others and we have found that PHP-Ib is caused by maternally inherited microdeletions that disrupt the imprinting of the GNAS complex locus. Various deletions within the GNAS locus itself or the neighboring STX16 gene have been identified, with the most frequent mutation being a 3-kb deletion removing STX16 exons 46. PHP-Ic is a PHP variant clinically similar to PHP-Ia, but erythrocyte Gsα activity appears normal in these patients, particularly when direct Gsα stimulators are used in the assay. Several PHP-Ic cases are caused by coding Gsα mutations that disrupt receptor coupling but not basal activation. In addition to Gsα, GNAS gives rise to several gene products that show exclusive monoallelic expression. Gsα, however, is expressed biallelically in most tissues; however, its expression is monoallelic in certain hormone responsive tissues, including renal proximal tubules and thyroid. The paternal Gsα allele is silenced in those tissues, allowing a heterozygous maternal mutation to result in a dramatic reduction in Gsα level/activity. The tissue-specific monoallelic Gsα expression explains the imprinted mode of inheritance for the hormone resistance in PHP type I. Data from reported patients with PHP-Ia or PHP-Ib indicate that the clinical outcome of PTH resistance does not occur at birth but instead develops after infancy or even later in childhood. Our investigations using a mouse model of PHP-Ia/PPHP confirmed that proximal tubular PTH resistance develops gradually after birth. We furthermore showed that the maternal and paternal alleles contribute equally to Gsα expression at birth but the paternal allele is silenced gradually after the early postnatal period in the renal proximal tubule. In contrast, the paternal Gsα silencing is already established in neonatal mouse brown fat. The delay of the allelic Gsα silencing in the renal proximal tubule could explain the latency of PTH resistance in PHP-Ia, although other possible mechanisms exist.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology