Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous Gαs disruption.

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