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.
- genetic mutations
- imprinting defects
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BL and EF-R contributed equally to this work.
Funding GPN is supported by Miguel Servet contracts from the Instituto de Salud Carlos III of the Spanish Ministry of Health (grant CP03/0064). This work was partially funded by grant GV2008/111035 from the Department of Health of the Basque Government and BIO08/ER/001. This group is also supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII. This work was also funded, in part, by grant number R01DK073911 from the National Institute of Diabetes and Digestive and Kidney Diseases (to MB) and from the German Ministry of Research and Education (GMG01GM0315 to OH). Other Funders: National Institutes of Health.
Competing interests None to declare.
Patient consent Obtained
Ethics approval This study was conducted with the approval of the Hospital de Cruces Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.