A New Deletion Ablating NESP55 Causes Loss of Maternal Imprint of A/B GNAS and Autosomal Dominant Pseudohypoparathyroidism Type Ib

Background: Patients with pseudohypoparathyroidism type Ib (PHP-1b) develop resistance toward PTH, leading to hypocalcemia and hyperphosphatemia. PHP-1b is an imprinted human disorder associated with methylation changes at one or several differentially methylated regions at the GNAS locus. This complex locus gives rise to several different transcripts with different patterns of imprinted expression depending on promoter methylation. They can be either coding [Gαs, XLαs, and neuroendocrine secretory protein-55 (NESP55)] or nontranslated (A/B and AS). The paternal AS transcript lies antisense to nesp55. Objective: Define the genetic defect in a new family with three patients presenting autosomal dominant PHP-1b. Design: We used methylation analysis, comparative genomic hybridization, and genotyping to characterize the defect. AS expression was studied in two patients and their unaffected mothers. Results: A novel deletion of 18,988 bp that removes NESP55 and a large part of its counterpart GNAS AS intron 4 ...