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Hospital de Órbigo, Spain

Fernandez-Rebollo E.,Harvard University | Perez De Nanclares G.,Research Unit | Lecumberri B.,Hospital Universitario La Paz | Turan S.,Harvard University | And 6 more authors.
Journal of Bone and Mineral Research

Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. Copyright © 2011 American Society for Bone and Mineral Research. Source

Lecumberri B.,Hospital Universitario La Paz | Fernandez-Rebollo E.,Endocrinology and Diabetes Research Group | Fernandez-Rebollo E.,Harvard University | Sentchordi L.,Hospital Universitario Of Guadalajara | And 12 more authors.
Journal of Medical Genetics

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 Gsa 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. Source

Shimomura K.,Oxford Genetics | De Nanclares G.P.,Endocrinology and Diabetes Research Group | Foutinou C.,Oxford Genetics | Caimari M.,Paediatric Endocrinology | And 2 more authors.
Diabetic Medicine

Background Closure of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel plays a key role in insulin secretion from the pancreatic β-cells. Many mutations in KCNJ11 and ABCC8, which respectively encode the pore-forming (Kir6.2) and regulatory (SUR1) subunits of the K ATP channel, cause neonatal diabetes. All such mutations impair the ability of metabolically generated ATP to close the channel. Although lysine 185 is predicted to be a major contributor to the ATP-binding site of Kir6.2, no mutations at this residue have been found to cause neonatal diabetes to date. Methods We report a 3-year-old girl with permanent neonatal diabetes (PNDM) caused by a novel heterozygous mutation (K185Q) at residue K185 of KCNJ11. The patient presented with marked hyperglycaemia and ketoacidosis at 70 days after birth, and insulin therapy was commenced. Results Wild-type and mutant K ATP channels were expressed in Xenopus oocytes and the effects of intracellular ATP on macroscopic KATP currents in inside-out membrane patches were measured. In the simulated heterozygous state, the K185Q mutation caused a substantial reduction in the ability of MgATP to inhibit the channel. Heterozygous K185Q channels were still blocked effectively by the sulphonylurea tolbutamide. Conclusions We report the first clinical case of a PNDM caused by a mutation at K185. Functional studies indicate that the K185Q mutation causes PNDM by reducing the ATP sensitivity of the KATP channel, probably via a reduction in ATP binding to Kir6.2. Based on the experimental data, the patient was successfully transferred to sulphonylurea therapy. © 2010 Diabetes UK. Source

Perez-Nanclares G.,Endocrinology and Diabetes Research Group | Romanelli V.,Hospital Universitario La Paz | Romanelli V.,Institute Salud Carlos III | Mayo S.,Hospital Universitario La Paz | And 75 more authors.
Journal of Clinical Endocrinology and Metabolism

Context: Genomic imprinting is the modification of the genomeso that genes from only one (rather than two) of the parental alleles are expressed.The mechanism underlying imprinting is epigenetic, occurring via changes in DNA methylation and histone modifications rather than through alterations in the DNA sequence. To date, nine different imprinting disorders have been clinically and genetically identified and a considerable research effort has been focused on determining the cause of the corresponding methylation defects. Objective: Our objective was to identify multilocus imprinting defects and characterize any mutations in trans-acting genes in patients with pseudohypoparathyroidism (PHP) caused by epigenetic alterations at GNAS locus. Design: We have investigated multilocus imprinting defects in 22 PHP patients with aberrant methylation at the GNAS locus not due to previously described deletions or to paternal uniparental disomy (UPD) of chromosome 20. Results: We found that, in contrast to what has been described in growth disorders, multilocus hypomethylation is an uncommon event in PHP patients. We were also unable to identify any genetic alteration causative of the epigenetic defects in the currently known methylation regulatory genes. Conclusion: Our work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS. Copyright © 2012 by The Endocrine Society. Source

Swift P.G.F.,Royal Infirmary | Skinner T.C.,Combined Universities Center for Rural Health | de Beaufort C.E.,Center Hospitalier Of Luxembourg | Cameron F.J.,Royal Melbourne Hospital | And 20 more authors.
Pediatric Diabetes

Objective: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control.Methods: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally.Results: A total of 2062 adolescents completed questionnaires (age 14.4 ± 2.3 yr; diabetes duration 6.1 ± 3.5 yr). Mean HbA 1c = 8.2 ± 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001).Conclusions: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres. © 2009 John Wiley & Sons A/S. Source

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