Deletion of the Noncoding GNAS Antisense Transcript Causes Pseudohypoparathyroidism Type Ib and Biparental Defects of GNAS Methylation in cis
S Chillambhi, S Turan, DY Hwang… - The Journal of …, 2010 - academic.oup.com
S Chillambhi, S Turan, DY Hwang, HC Chen, H Jüppner, M Bastepe
The Journal of Clinical Endocrinology & Metabolism, 2010•academic.oup.comContext: GNAS encodes the α-subunit of the stimulatory G protein as well as additional
imprinted transcripts including the maternally expressed NESP55 and the paternally
expressed XLαs, antisense, and A/B transcripts. Most patients with
pseudohypoparathyroidism type Ib (PHP-Ib) exhibit imprinting defects affecting the maternal
GNAS allele, which are thought to reduce/abolish Gsα expression in renal proximal tubules
and thereby cause resistance to PTH. Objective: Our objective was to define the genetic …
imprinted transcripts including the maternally expressed NESP55 and the paternally
expressed XLαs, antisense, and A/B transcripts. Most patients with
pseudohypoparathyroidism type Ib (PHP-Ib) exhibit imprinting defects affecting the maternal
GNAS allele, which are thought to reduce/abolish Gsα expression in renal proximal tubules
and thereby cause resistance to PTH. Objective: Our objective was to define the genetic …
Context: GNAS encodes the α-subunit of the stimulatory G protein as well as additional imprinted transcripts including the maternally expressed NESP55 and the paternally expressed XLαs, antisense, and A/B transcripts. Most patients with pseudohypoparathyroidism type Ib (PHP-Ib) exhibit imprinting defects affecting the maternal GNAS allele, which are thought to reduce/abolish Gsα expression in renal proximal tubules and thereby cause resistance to PTH.
Objective: Our objective was to define the genetic defect in a previously unreported family with autosomal dominant PHP-Ib.
Design and Setting: Analyses of serum and urine chemistries and of genomic DNA and lymphoblastoid-derived RNA were conducted at a tertiary hospital and research laboratory.
Patients: Affected individuals presented with muscle weakness and/or paresthesia and showed hypocalcemia, hyperphosphatemia, and elevated serum PTH. Obligate carriers were healthy and revealed no obvious abnormality in mineral ion homeostasis.
Results: A novel 4.2-kb microdeletion was discovered in the affected individuals and the obligate carriers, ablating two noncoding GNAS antisense exons while preserving the NESP55 exon. On maternal transmission, the deletion causes loss of all maternal GNAS imprints, partial gain of NESP55 methylation, and PTH resistance. Paternal transmission of the mutation leads to epigenetic alterations in cis, including a partial loss of NESP55 methylation and a partial gain of A/B methylation.
Conclusions: The identified deletion points to a unique cis-acting element located telomeric of the NESP55 exon that is critical for imprinting both GNAS alleles. These findings provide novel insights into the molecular mechanisms underlying PHP and GNAS imprinting.
Oxford University Press