Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis

Smitha Chillambhi, Serap Turan, Daw Yang Hwang, Hung Chun Chen, Harald Jüppner, Murat Bastepe

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3993-4002
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number8
DOIs
StatePublished - Jan 1 2010

Fingerprint

Pseudohypoparathyroidism
Methylation
Exons
Mothers
Defects
Alleles
Hyperphosphatemia
Hospital Laboratories
Proximal Kidney Tubule
Hypocalcemia
Paresthesia
Muscle Weakness
Research laboratories
Serum
GTP-Binding Proteins
Tertiary Care Centers
Epigenomics
Minerals
Muscle
Homeostasis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis. / Chillambhi, Smitha; Turan, Serap; Hwang, Daw Yang; Chen, Hung Chun; Jüppner, Harald; Bastepe, Murat.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 8, 01.01.2010, p. 3993-4002.

Research output: Contribution to journalArticle

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AU - Jüppner, Harald

AU - Bastepe, Murat

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