Coexistence of two different pseudohypoparathyroidism subtypes (Ia and Ib) in the same kindred with independent Gsα coding mutations and GNAS imprinting defects. Issue 4 (26th October 2009)

• Record Type: Journal Article
• Authors: Lecumberri, B; Fernández-Rebollo, E; Sentchordi, L; Saavedra, P; Bernal-Chico, A; Pallardo, L F; Bustos, J M Jiménez; Castaño, L; de Santiago, M; Hiort, O; Pérez de Nanclares, G; Bastepe, M
• Is Part Of: Journal of medical genetics. Volume 47:Issue 4(2010)
• Page Start: 276
• Page End: 280
• Publication Date: 2009-10-26
• Subjects: Pseudohypoparathyroidism -- PHP-Ia -- PHP-Ib -- genetic mutations -- imprinting defects -- endocrinology -- genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2009.071001
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Pseudohypoparathyroidism (PHP) defines a rare group of disorders whose common feature is resistance to the parathyroid hormone. Patients with PHP-Ia display additional hormone resistance, Albright 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 parathyroid hormone 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. Patients: Two unrelated PHP families, each of which includes at least one patient with a Gsα coding mutation and another with GNAS loss of imprinting, are reported here. Results: 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. Conclusions: These molecular data reveal an interesting mixture, in the same family, of both genetic and epigenetic mutations of the same gene.