title: Different pattern of epigenetic changes of the GNAS gene locus in patients with pseudohypoparathyroidism type Ic confirm the heterogeneity of underlying pathomechanisms in this subgroup of pseudohypoparathyroidism and the demand for a new classification of GNAS-related disorders.
abstract: BACKGROUND
  Disorders characterized by PTH resistance are grouped within the term pseudohypoparathyroidism type I (PHPI). Most subtypes of this disease are caused by genetic or epigenetic changes of the GNAS locus leading to deficiency of the α-subunit of stimulatory G proteins (Gsα). Because the in vitro measured Gsα protein activity is normal in pseudohypoparathyroidism Ic (PHPIc), it had previously been postulated that this subtype is caused by impairment of distinct components of the G protein-signaling pathway. However, recently, pathogenic GNAS mutations in a subset of PHPIc patients were found.
  
  
  OBJECTIVE
  To clarify the underlying pathogenic mechanism of GNAS exon 1-13 mutation-negative PHPIc cases by investigating the differentially methylated regions of GNAS for epigenetic abnormalities.
  
  
  METHODS
  The methylation pattern of GNAS exons A/B, AS, XL, and NESP from blood-derived leukocytes of 26 PHPIc patients was assessed by pyrosequencing of bisulfite-converted DNA.
  
  
  RESULTS
  Six patients presented with three different patterns of epigenetic changes. One patient had an exclusive loss of methylation of exon A/B associated with a STX16 deletion; four patients had an additional loss of methylation in XL and AS and a gain of methylation in NESP; and one patient presented with partial GNAS methylation changes concerning all differentially methylated regions.
  
  
  CONCLUSIONS
  Our results confirm that PHPIc is a heterogeneous entity caused in part by impaired Gsα function, not only due to mutations, but also due to abnormal imprinting of GNAS. However, in the majority of cases of PHPIc, the underlying etiopathogenesis remains elusive.
authors.affiliation: Division of Experimental Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Brix
authors.forename: Ralf
authors.initials: R
authors.lastname: Werner
authors.forename: Pia
authors.initials: P
authors.lastname: Staedt
authors.forename: Dagmar
authors.initials: D
authors.lastname: Struve
authors.forename: Olaf
authors.initials: O
authors.lastname: Hiort
authors.forename: Susanne
authors.initials: S
authors.lastname: Thiele
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D015331:Cohort Studies; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D018740:Genetic Heterogeneity; D056426:Genetic Loci; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011547:Pseudohypoparathyroidism / Q000145:classification* / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs