A Novel GNAS Duplication Associated With Loss-of-Methylation Restricted to Exon A/B Causes Pseudohypoparathyroidism Type Ib (PHP1B)

J Bone Miner Res. 2021 Mar;36(3):546-552. doi: 10.1002/jbmr.4209. Epub 2020 Nov 28.

Abstract

Pseudohypoparathyroidism type Ib (PHP1B) is characterized by resistance to parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia, and in some cases resistance toward additional hormones. Patients affected by this disorder all share a loss-of-methylation (LOM) at the differentially methylated GNAS exon A/B, which reduces expression of the stimulatory G protein α-subunit (Gsα) from the maternal allele. This leads in the proximal renal tubules, where the paternal GNAS allele does not contribute much to expression of this signaling protein, to little or no Gsα expression thereby causing PTH resistance. We now describe a PHP1B patient with a de novo genomic GNAS duplication of approximately 88 kb, which is associated with LOM restricted to exon A/B alone. Multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), and whole-genome sequencing (WGS) established that the duplicated DNA fragment extends from GNAS exon AS1 (telomeric breakpoint) to a small region between two imperfect repeats just upstream of LOC105372695 (centromeric breakpoint). Our novel duplication is considerably shorter than previously described duplications/triplications in that portion of chromosome 20q13 and it does not affect methylation at exons AS and XL. Based on these and previous findings, it appears plausible that the identified genomic abnormality disrupts in cis the actions of a transcript that is required for establishing or maintaining exon A/B methylation. Our findings extend the molecular causes of PHP1B and provide additional insights into structural GNAS features that are required for maintaining maternal Gsα expression and for preventing PTH-resistance. © 2020 American Society for Bone and Mineral Research (ASBMR).

Keywords: CELL/TISSUE SIGNALING; DISORDERS OF CALCIUM/PHOSPHATE METABOLISM; ENDOCRINE PATHWAYS; EPIGENETICS; GENETIC RESEARCH; PARATHYROID-RELATED DISORDERS; PTH/Vit D/FGF23.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromogranins* / genetics
  • Comparative Genomic Hybridization
  • DNA Methylation / genetics
  • Exons / genetics
  • Fibroblast Growth Factor-23
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Humans
  • Pseudohypoparathyroidism* / genetics

Substances

  • Chromogranins
  • FGF23 protein, human
  • Fibroblast Growth Factor-23
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs