Postnatal Establishment of Allelic Gαs Silencing as a Plausible Explanation for Delayed Onset of Parathyroid Hormone Resistance Owing to Heterozygous Gαs Disruption

Abstract

Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of Gαs activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH-resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH-resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH-resistance caused by the maternal loss of Gαs, i.e. hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (three-weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH-resistance in patients with PHP-Ia.

Diagnosis and Management of Congenital Hypothyroidism Associated with Pseudohypoparathyroidism

“…Resistance to TSH is a common finding in PHP1A patients, and hypothyroidism is one of the main symptoms of the multihormonal resistance in PHP, affecting more than 90% of PHP1A patients [1,3,17,21,22]. In 1982, Mallet et al [23] showed that there was no increase in intracellular cAMP in response to TSH in membrane thyroid from patients with PHP.…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…Evidence of TSH resistance is often present at birth and can lead to the misdiagnosis of congenital hypothyroidism 24,30 , whereas PTH resistance develops during childhood [31][32][33][34] . Similarly, brachydactyly develops progressively and usually becomes obvious before puberty 34,35 .…”

“…In patients with PHP1A, resistance to PTH is usually absent at birth and evolves over life (from 0.2 years to 22 years) 18,31,34 , while the clinical manifestations typically occur later. These data suggest that PTH resistance begins in early childhood, and the resultant changes in serum levels of calcium and phosphorus develop gradually, at some point during adulthood 31,32,[66][67][68] . The first biochemical abnormalities to become apparent are elevated serum levels of PTH and elevated serum levels of phosphorus, followed by hypocalcaemia.…”

Pseudohypoparathyroidism type 1a due to a novel mutation in the GNAS gene

“…Age of onset of the hormone resistance is quite variable among mutation‐positive individuals and can be delayed for several years. This latency of PTH resistance in patients with PHP1a has been attributed to a gradual development of paternal Gs‐alpha silencing in target tissues 4. Therefore, genetic screening of family members can be useful for presymptomatic diagnosis.…”