• Gustavo Perez-Nanclares, Valeria Romanelli, Sonia Mayo, Intza Garin, Celia Zazo, Eduardo Fernandez-Rebollo, Francisco Martínez, Pablo Lapunzina, Guiomar Pérez de Nanclares, and Spanish PHP Group.
• Molecular (Epi)Genetics Lab Research Unit, Hospital Txagorritxu, E-01009, Vitoria-Gasteiz, Alava, Spain.
• J. Clin. Endocrinol. Metab. 2012 Jun 1; 97 (6): E1060-7.

ContextGenomic imprinting is the modification of the genome so that genes from only one (rather than two) of the parental alleles are expressed. The mechanism underlying imprinting is epigenetic, occurring via changes in DNA methylation and histone modifications rather than through alterations in the DNA sequence. To date, nine different imprinting disorders have been clinically and genetically identified and a considerable research effort has been focused on determining the cause of the corresponding methylation defects.ObjectiveOur objective was to identify multilocus imprinting defects and characterize any mutations in trans-acting genes in patients with pseudohypoparathyroidism (PHP) caused by epigenetic alterations at GNAS locus.DesignWe have investigated multilocus imprinting defects in 22 PHP patients with aberrant methylation at the GNAS locus not due to previously described deletions or to paternal uniparental disomy (UPD) of chromosome 20.ResultsWe found that, in contrast to what has been described in growth disorders, multilocus hypomethylation is an uncommon event in PHP patients. We were also unable to identify any genetic alteration causative of the epigenetic defects in the currently known methylation regulatory genes.ConclusionOur work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS.

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