Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy

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 Gsα 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: Gsα 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 Gsα activity. Instead of Gsα 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 Gsα mutations have been excluded should be evaluated for epigenetic alterations within GNAS.