title: Pseudohypoparathyroidism type Ib associated with novel duplications in the GNAS locus.
abstract: BACKGROUND
  Pseudohypoparathyroidism type 1b (PHP-Ib) is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH) and absence of any features of Albright's hereditary osteodystrophy. Patients with PHP-Ib suffer of defects in the methylation pattern of the complex GNAS locus. PHP-Ib can be either sporadic or inherited in an autosomal dominant pattern. Whereas familial PHP-Ib is well characterized at the molecular level, the genetic cause of sporadic PHP-Ib cases remains elusive, although some molecular mechanisms have been associated with this subtype.
  
  
  OBJECTIVE
  The aim of the study was to investigate the molecular and imprinting defects in the GNAS locus in two unrelated patients with PHP-Ib.
  
  
  METHODS
  We have analyzed the GNAS locus by direct sequencing, Methylation-Specific Multiplex Ligation-dependent Probe Amplification, microsatellites, Quantitative Multiplex PCR of Short Fluorescent fragments and array-Comparative Genomic Hybridization studies in order to characterize two unrelated families with clinical features of PHP-Ib.
  
  
  RESULTS
  We identified two duplications in the GNAS region in two patients with PHP-Ib: one of them, comprising ∼ 320 kb, occurred 'de novo' in the patient, whereas the other one, of ∼ 179 kb in length, was inherited from the maternal allele. In both cases, no other known genetic cause was observed.
  
  
  CONCLUSIONS
  In this article, we describe the to-our-knowledge biggest duplications reported so far in the GNAS region. Both are associated to PHP-Ib, one of them occurring 'de novo' and the other one being maternally inherited.
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces, CIBERER, CIBERDEM, UPV-EHU, Barakaldo, Basque Country, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Perez-Nanclares
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces, CIBERER, CIBERDEM, UPV-EHU, Barakaldo, Basque Country, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Velayos
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces, CIBERER, CIBERDEM, UPV-EHU, Barakaldo, Basque Country, Spain.
authors.forename: Amaya
authors.initials: A
authors.lastname: Vela
authors.affiliation: Clinical Management Unit of Endocrinology and Nutrition, Hospital Universitario San Cecilio, Instituto de Investigacion Biosanitaria de Granada, Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Muñoz-Torres
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces, CIBERER, CIBERDEM, UPV-EHU, Barakaldo, Basque Country, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
mesh_terms: D000293:Adolescent; D000328:Adult; D002864:Chromogranins; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D020440:Gene Duplication; D006801:Humans; D008297:Male; D011547:Pseudohypoparathyroidism / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs