Lebrun M.,University of Caen Lower Normandy |
Richard N.,University of Caen Lower Normandy |
Abeguile G.,University of Caen Lower Normandy |
David A.,University of Nantes |
And 10 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010
Context: Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, and studies in different families have shown that POH is also caused by paternally inherited GNAS mutations. Objective: Our purpose was to characterize parental origin of the mutated allele in de novo cases of POH and to draw phenotype/genotype correlations according to maternal or paternal transmission of a same GNAS mutation. Design and Setting: We conducted a retrospective study on patients addressed to our referral center for the rare diseases of calcium and phosphorus metabolism. Patients and Methods: We matched 10 cases of POH with cases of pseudohypoparathyroidism type 1a carrying the same GNAS mutations. Main Outcome Measures: The parental origin of the mutated allele was studied using informative intragenic polymorphisms and subcloning of PCR products. Results: Paternal origin of GNAS mutations was clearly demonstrated in eight POH cases including one patient with mutation in exon 1. Genotype/phenotype analyses suggest that there is no direct correlation between the ossifying process and the position of the inactivating GNAS mutation. It is, however, more severe in patients in whom origin of the mutation is paternal. Severe intrauterine growth retardation was clearly evidenced in paternally inherited mutations. Conclusions: Clinical heterogeneity makes genetic counseling a delicate matter, especially in which paternal inheritance is concerned because it can lead to either a mild expression of pseudopseudohypoparathyroidism or a severe expression of POH. Copyright © 2010 by The Endocrine Society.
Richard N.,Caen University Hospital Center |
Richard N.,Reference Center for Rare Disorders of Calcium and Phosphorus Metabolism |
Abeguile G.,Caen University Hospital Center |
Abeguile G.,Reference Center for Rare Disorders of Calcium and Phosphorus Metabolism |
And 14 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012
Background: Patients with pseudohypoparathyroidism type Ib (PHP-1b) develop resistance toward PTH, leading to hypocalcemia and hyperphosphatemia. PHP-1b is an imprinted human disorder associated with methylation changes at one or several differentially methylated regions at the GNAS locus. This complex locus gives rise to several different transcripts with different patterns of imprinted expression depending on promoter methylation. They can be either coding [Gas, XLas, and neuroendocrine secretory protein-55 (NESP55)] or nontranslated (A/Band AS). The paternal AS transcript lies antisense to nesp55. Objective: Define the genetic defect in a new family with three patients presenting autosomal dominant PHP-1b. Design: We used methylation analysis, comparative genomic hybridization, and genotyping to characterize the defect. AS expression was studied in two patients and their unaffected mothers. Results: A novel deletion of 18,988 bpthat removes NESP55 and a large part of its counterpart GNAS AS intron 4 was discovered. On maternal transmission, this deletion causes loss of A/B methylation without affecting XL/AS imprint. On paternal transmission, there are no methylation anomalies. The deletion creates a cryptic exon contained within AS intron 4, which is expressed from the mutated allele, be it paternal or maternal. Conclusion: This new deletion suggests that NESP55 is an additional imprinting control region that directs A/B methylation in humans. We bring arguments in support of the theory of reciprocal inhibition between the expression of NESP and AS. However, determining whether loss of methylation at the A/B differentially methylated region is a consequence of the loss of NESP expression or of the expression of AS requires additional investigations. Copyright © 2012 by The Endocrine Society.