Coexistence of two different pseudohypoparathyroidism subtypes (Ia and Ib) in the same kindred with independent Gs{alpha} coding mutations and GNAS imprinting defects

• Published in: Journal of medical genetics Vol. 47; no. 4; p. 276
• Main 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
• Format: Journal Article
• Language: English
• Published: England 01-04-2010
• Subjects: Adult; Chromogranins; DNA Methylation; DNA Mutational Analysis; Female; Gene Dosage; Genomic Imprinting; GTP-Binding Protein alpha Subunits, Gs - genetics; Haplotypes; Humans; Male; Microsatellite Repeats; Middle Aged; Mutation; Pedigree; Polymerase Chain Reaction; Pseudohypoparathyroidism - genetics
• ISSN: 1468-6244
• DOI: 10.1136/jmg.2009.071001

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 Gsalpha activity in easily accessible cells. This form of PHP is associated with heterozygous inactivating mutations in Gsalpha-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 Gsalpha activity. Instead of coding Gsalpha mutations, patients with PHP-Ib display imprinting defects of GNAS, caused, at least in some cases, by genetic mutations within or nearby this gene.
Two unrelated PHP families, each of which includes at least one patient with a Gsalpha coding mutation and another with GNAS loss of imprinting, are reported here.
One of the patients with GNAS imprinting defects has paternal uniparental isodisomy of chromosome 20q, explaining the observed imprinting abnormalities. The identified Gsalpha 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.