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Epigenetic Defects of GNAS in Patients with Pseudohypoparathyroidism and Mild Features of Albright’s Hereditary Osteodystrophy

Endocrinology and Diabetes Research Unit (G.P.d.N., E.F.-R., I.S., S.G., J.R.B., N.Z., L.C.), Hospital de Cruces, Barakaldo E48903, Basque Country, Spain; Pediatric Endocrinology Unit (B.G.-C.), Severo Ochoa Hospital, Leganés, 28911 Madrid, Spain; Departments of Medicine, Nursing, and Pediatrics (S.G., J.R.B., L.C.), University of Basque Country, 48940 Leioa, Bizkaia, Spain; Endocrinology Service (E.M.), Hospital de Navarra, 31080 Pamplona, Spain; Endocrinology Service (M.J.M.), Hospital do Meixoeiro, 36200 Viga, Pontevedra, Spain; Pediatric Endocrinology, Growth, and Adolescence Unit (M.P.), Clinical University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain; Fundación Pública Galega de Medicina Xenómica (F.B.), 15706 Santiago de Compostela, A Coruña, Spain; Department of Pediatric and Adolescent Medicine (W.A., O.H.), University of Lübeck, 23538 Lübeck, Germany; and Endocrine Unit (H.J., M.B.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Luis Castaño, M.D., Ph.D., Endocrinology and Diabetes Research Group, Hospital de Cruces, Cruces-Barakaldo E48903 Bizkaia, Basque Country, Spain. E-mail: lcastano{at}hcru.osakidetza.net; or Murat Bastepe, M.D., Ph.D., Endocrine Unit, Massachusetts General Hospital, 50 Blossom Street, Thier 10, Boston, Massachusetts 02114. E-mail: bastepe{at}helix.mgh.harvard.edu.

Context: Several endocrine disorders that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). PHP type I, associated with blunted PTH-induced nephrogenous cAMP formation and phosphate excretion, is subdivided according to the presence or absence of additional endocrine abnormalities, Albright’s hereditary osteodystrophy (AHO), and reduced Gs activity caused by GNAS mutations.

Objective: We sought to identify the molecular defect in four unrelated patients who were thought to have PHP-Ia because of PTH and TSH resistance and mild AHO features.

Methods: Gs activity and mutation analysis, and assessment of GNAS haplotype, methylation, and gene expression were performed for probands and family members.

Results: Two patients showed modest decreases in erythrocyte Gs activity. Instead of Gs point mutations, however, all four patients showed methylation defects of the GNAS locus, a feature previously described only for PHP-Ib. Furthermore, one patient with an isolated loss of GNAS exon A/B methylation had the 3-kb STX16 deletion frequently identified in PHP-Ib patients. In all but one of the remaining patients, haplotype analysis excluded large deletions or uniparental disomy as the cause of the observed methylation changes.

Conclusions: Our investigations indicate that an overlap may exist between molecular and clinical features of PHP-Ia and PHP-Ib. No current mechanisms can explain the AHO-like features of our patients, some of which may not be linked to GNAS. Therefore, patients with hormone resistance and AHO-like features in whom coding Gs mutations have been excluded should be evaluated for epigenetic alterations within GNAS.

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