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Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib

  1. Murat Bastepea,2
  1. aEndocrine Unit, Department of Medicine, and
  2. gPediatric Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
  3. bPediatric Endocrinology, Marmara University School of Medicine, Istanbul 34899, Turkey;
  4. cInstitute of Pathology, Medical University of Graz, 8036 Graz, Austria;
  5. dCellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom;
  6. eEpigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom; and
  7. fCentre for Trophoblast Research, University of Cambridge, Cambridge CB2 1TN, United Kingdom

  1. Edited* by John T. Potts, Massachusetts General Hospital, Charlestown, MA, and approved March 19, 2012 (received for review October 25, 2011)

Abstract

Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55/ASdel3-4m, delNASm) from the GNAS locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-IbdelNASm), a disorder of proximal tubular parathyroid hormone (PTH) resistance associated with loss of maternal GNAS methylation imprints. Mice carrying a similar, maternally inherited deletion of the Nesp55 DMR (ΔNesp55m) replicate these Gnas epigenetic abnormalities and show evidence for PTH resistance, yet these mice demonstrate 100% mortality during the early postnatal period. We investigated whether the loss of extralarge αs (XLαs) imprinting and the resultant biallelic expression of XLαs are responsible for the early postnatal lethality in ΔNesp55m mice. First, we found that ΔNesp55m mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the ΔNesp55m mice but with normalized XLαs expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (ΔNesp55m/Gnasxlm+/p−) showed nearly 100% survival up to postnatal day 10, and a substantial number of them lived to adulthood. The hypoglycemia and reduced stomach-to-body weight ratio observed in 2-d-old ΔNesp55m mice were rescued in the ΔNesp55m/Gnasxlm+/p− mice. Surviving double-mutant animals had significantly reduced Gαs mRNA levels and showed hypocalcemia, hyperphosphatemia, and elevated PTH levels, thus providing a viable model of human AD-PHP-Ib. Our findings show that the hypoglycemia and early postnatal lethality caused by the maternal deletion of the Nesp55 DMR result from biallelic XLαs expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.

Footnotes

  • ↵1Present address: Diabetes and Obesity Laboratory, Endocrinology and Nutrition Unit, Institut d’Investigations Biomediques August Pi i Sunyer, Hospital Clinic de Barcelona, 08028 Barcelona, Spain.

  • ↵2To whom correspondence should be addressed. E-mail: bastepe{at}helix.mgh.harvard.edu.

  • Author contributions: E.F.-R., H.J., and M.B. designed research; E.F.-R., A.M., M.R., and S.T. performed research; L.F.F., A.P., and G.K. contributed new reagents/analytic tools; E.F.-R., A.M., H.J., and M.B. analyzed data; and E.F.-R., H.J., and M.B. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1117608109/-/DCSupplemental.

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