title: Intragenic GNAS deletion involving exon A/B in pseudohypoparathyroidism type 1A resulting in an apparent loss of exon A/B methylation: potential for misdiagnosis of pseudohypoparathyroidism type 1B.
abstract: BACKGROUND
  Several endocrine diseases that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). Patients with PHP type Ia show additional hormone resistance, defective erythrocyte G(s)alpha activity, and dysmorphic features termed Albright's hereditary osteodystrophy (AHO). Patients with PHP-Ib show less diverse hormone resistance and normal G(s)alpha activity; AHO features are typically absent in PHP-Ib. Mutations affecting G(s)alpha coding exons of GNAS and epigenetic alterations in the same gene are associated with PHP-Ia and -Ib, respectively. The epigenetic GNAS changes in familial PHP-Ib are caused by microdeletions near or within GNAS but without involving G(s)alpha coding exons.
  
  
  OBJECTIVE
  We sought to identify the molecular defect in a patient who was diagnosed with PHP-Ia based on clinical presentation (hormone resistance and AHO) but displayed the molecular features typically associated with PHP-Ib (loss of methylation at exon A/B) without previously described genetic mutations.
  
  
  METHODS
  Microsatellite typing, comparative genome hybridization, and allelic dosage were performed for proband and her parents.
  
  
  RESULTS
  Comparative genome hybridization revealed a deletion of 30,431 bp extending from the intronic region between exons XL and A/B to intron 5. The same mutation was also demonstrated, by PCR, in the patient's mother, but polymorphism and allele dosage analyses indicated that she had this mutation in a mosaic manner.
  
  
  CONCLUSIONS
  We discovered a novel multiexonic GNAS deletion transmitted to our patient from her mother who is mosaic for this mutation. The deletion led to different phenotypic manifestations in the two generation and appeared, in the patient, as loss of GNAS imprinting.
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital de Cruces, 48903 Barakaldo, Bizkaia, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernandez-Rebollo
authors.forename: Beatriz
authors.initials: B
authors.lastname: García-Cuartero
authors.forename: Intza
authors.initials: I
authors.lastname: Garin
authors.forename: Cristina
authors.initials: C
authors.lastname: Largo
authors.forename: Francisco
authors.initials: F
authors.lastname: Martínez
authors.forename: Concepcion
authors.initials: C
authors.lastname: Garcia-Lacalle
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
authors.forename: Guiomar
authors.initials: G
authors.lastname: Pérez de Nanclares
mesh_terms: D001483:Base Sequence; D002864:Chromogranins; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D003951:Diagnostic Errors; D005091:Exons; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011547:Pseudohypoparathyroidism / Q000175:diagnosis / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs