Abstract

Pseudohypoparathyroidism (PHP) defines a rare group of disorders whose common feature is resistance to parathyroid hormone. Patients with PHP-Ia display additional hormone resistance, Albright's hereditary osteodystrophy (AHO), and reduced Gsα activity in easily accessible cells. This form of PHP is associated with heterozygous inactivating mutations in Gsα-coding exons of GNAS, an imprinted gene locus on chromosome 20q13.3. Patients with PHP-Ib typically have isolated PTH resistance, lack AHO features, and demonstrate normal erythrocyte Gsα activity. Instead of coding Gsα mutations, patients with PHP-Ib display imprinting defects of GNAS caused, at least in some cases, by genetic mutations within or nearby this gene. We now report two unrelated PHP families, each of which include at least one patient with a Gsα coding mutation and another with GNAS loss of imprinting. One of the patients with GNAS imprinting defects has paternal uniparental isodisomy of chromosome 20q, explaining the observed imprinting abnormalities. The identified Gsα coding mutations include a tetranucleotide deletion in exon 7, which is frequently found in PHP-Ia, and a novel single nucleotide change at the acceptor splice junction of intron 11. These molecular data reveal an interesting mixture, in the same family, of both genetic and epigenetic mutations of the same gene.