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Correspondence to Author: Sonica veyes, 

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

ABSTRACT: 
The hallmarks of pseudohypoparathyroidism type Ib (PHP1B) include resistance to parathyroid hormone (PTH), which causes hyperphosphatemia and hypocalcemia, as well as occasionally resistance to other hormones. A lossof-methylation (LOM) at the differentially methylated GNAS exon A/B is a common feature among patients with this condition, since it lowers the production of the stimulatory G protein α-subunit (Gsα) from the maternal allele. In the proximal renal tubules, where the paternal GNAS allele has a negligible effect on the expression of this signaling protein, this results in little to no expression of Gsα, which causes PTH resistance. We now present the case of PHP1B patient with a de novo genomic GNAS duplication of about 88 kb linked to LOM limited to exon A/B.Comparative genomic hybridization (CGH), whole-genome sequencing (WGS), and multiplex ligation-dependent probe amplification (MLPA) all confirmed that the duplicated DNA fragment extends from GNAS exon AS1 (telomeric breakpoint) to a brief area between two imperfect repeats, directly upstream of LOC105372695 (centromeric breakpoint). Our unique duplication is significantly shorter than the duplications/triplications in that region of chromosome 20q13 that have been previously reported, and it has no effect on the methylation at exons AS and XL. It is likely that the detected genetic aberration interferes with a transcript’s ability to create or sustain exon A/B methylation in cis, based on these and other studies. Our research expands on the molecular reasons of PHP1B and offers further understanding of the structural GNAS characteristics needed to preserve maternal Gsα expression and avoid PTH resistance. Copyright 2020 The American Society for Mineral Research (ASBMR) All rights reserved.

Citation:

Sonica veyes. Type Ib of pseudohypoparathyroidism is caused by a novel GNAS duplication associated with a loss-of-methylation limited to exons A and B (PHP1B). The Journal of Bone and Mineral Research 2024.