ECE2009 Poster Presentations Bone/Calcium (42 abstracts)
Clinical and molecular characterization of Spanish patients with pseudohypoparathyroidism
Maria Dolores Moure 1 , Eduardo Fernandez-Rebollo 1 , Sonia Gaztambide 1, , Gustavo Perez-Nanclares 1 , Luis Castano 1, , Guiomar Perez de Nanclares 1, & Spanish PHP Group 1
1Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, Bizkaia, Spain; 2CIBERER, Barakaldo, Bizkaia, Spain.
Pseudohypoparathyroidism (PHP) is a term applied to a heterogeneous group of disorders whose common feature is resistance to parathyroid hormone. Most of the PHP forms are caused by defects in GNAS: PHP-Ia (characterized by PTH and TSH resistance with Albright Hereditary Osteodystrophy) is caused by heterozygous inactivating mutations in those exons of GNAS encoding the α subunit of the stimulatory G-protein, and the autosomal dominant form of PHP-Ib (PTH and TSH resistance without phenotypic manifestations) is caused by alteration in the methylation pattern of the locus, usually associated with microdeletions at STX16 gene that are maternally transmitted.
Aim: To analyze the complete GNAS locus, including deletions at STX16, in order to investigate the underlying molecular mechanisms involved in the etiology of pseudohypoparathyroidism.
Methods: Gsα activity, GNAS mutation and haplotype, and GNAS methylation analyses were performed for the probands and family members.
Results: The genetic and epigenetic study of 60 PHP patients revealed 25 point mutations (all associated with PHP-Ia), two paternal 20qUPD (one PHP-Ia and one PHP-Ib) and 23 loss of imprinting at GNAS locus (nearly half of them associated with PHP-Ia), only 5 associated to previously described STX16 deletions. A 2q37 deletion was also identified.
Very preliminary studies on genotype–phenotype correlations showed that patients with epigenetic alterations are diagnosed latter than those with genetic mutations.
Conclusion: There seems to be an overlap between the molecular and clinical features of PHP-Ia and PHP-Ib as molecular alterations previously associated with PHP-Ib are also present in patients diagnosed as PHP-Ia.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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