Etablierung eines Mausmodels für PHP-Ib (Pseudohypoparathyreoidismus Typ 1-b) zur Erforschung der Mechanismen die zu PTH-Resistenz führen.

Pseudohypoparathyroidism type-Ib (PHP-Ib) is characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH). Furthermore, this defect was shown to be correlated with paternal imprinting and that affected individuals, but not unaffected carriers, exhibit a loss of methylation at exon A/B. Exon A/B comprises a differentially methylated region (GNAS-DMR) located upstream of the promoter of Gsalpha which encodes an alternative noncoding GNAS transcript. Recently, we identified an ~4.5 kb microdeletion affecting the DMR of NESP55, another further upstream located first exon of GNAS, for an autosomal dominant form of PHP-Ib (AD-PHP-Ib). The NESP55-DMR is thought to disrupt an imprinting control element regulating methylation at exon A/B, thereby silencing Gsalpha expression in the renal cortex and leading to hormonal resistance. To further explore the mechanisms underlying the epigenotypic regulation of exon A/B and the resulting development of PTH-resistance in the proximal renal tubules, we generated mice, named Nesp DMR∆, with the equivalent of the human deletion identified in AD-PHP-Ib.

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