Multiple hormonal resistances: Diagnosis, evaluation and therapy.

Molecular alterations of cAMP-mediated signaling affect primarily the signaling of the PTH/PTHrp receptor, and, with different severities the signaling of other hormones, including TSH. The identification of PTH and other hormonal resistances implies to look for the genetic disorder supporting the metabolic disorder.

GNAS -Related Loss-of-Function Disorders and the Role of Imprinting.

GNAS (guanine nucleotide-binding protein, α stimulating) is a complex imprinted locus coding, besides the α-stimulatory subunit of the G protein, the paternally (extra-large, antisense and A/B) and maternally (neuroendocrine secretory protein) transcripts. Heterozygous mutations in the coding sequence of GNAS produce dominant phenotypes (combination of resistances to hormones signaling through G-protein-coupled receptors, osteodystrophy and obesity) that depend on the parental origin of the mutated allele. Likewise, alterations in the methylation at promoters of GNAS transcripts, associated or not with deletions of imprinting control regions in the nearby STX16 gene or within GNAS, prompt resistance to parathormone when affecting the maternal allele.