title: GNAS1 mutational analysis in pseudohypoparathyroidism.
abstract: OBJECTIVE
  Mutations of the GNAS1 gene, which is located on chromosome 20q13.11 and encodes the alpha-subunit of the stimulatory GTP-binding protein, have been identified in patients with pseudohypoparathyroidism type Ia (PHPIa) and pseudopseudohypoparathyroidism (PPHP). We have undertaken studies to determine the prevalence of GNAS1 mutations and to explore methods for their more rapid detection.
  
  
  METHODS
  Thirteen unrelated families (8 with PHPIa and PPHP patients, and 5 with PPHP patients only) were investigated for GNAS1 mutations in the 1050 base-pair (bp) region spanning exons 2-13 by single-stranded conformational polymorphism (SSCP) and DNA sequence analysis.
  
  
  RESULTS
  GNAS1 mutations were detected in 4 of the 8 families with PHPIa patients. These consisted of: two novel de novo missense mutations (Pro115Ser and Glu259Val) in two families and an identical 4 bp deletion of codons 189 and 190 resulting in a frame-shift in two unrelated families. These results expand the spectrum of GNAS1 mutations associated with this disorder and confirm the presence of a mutational hot-spot involving codons 189 and 190. SSCP analysis was found to be a specific and sensitive method that detected all 4 mutations. GNAS1 mutations were not detected in any of the PPHP only families.
  
  
  CONCLUSIONS
  The pseudohypoparathyroid disorders appear to represent a heterogeneous group with GNAS1 mutations forming the molecular aetiology in approximately 50% of pseudohypoparathyroidism type Ia families. Such mutations can be reliably identified by single-stranded conformational polymorphism and this will help to supplement the clinical evaluation of some patients and their families, particularly as the disease may not be fully penetrant.
authors.affiliation: MRC Molecular Endocrinology Group, Imperial College School of Medicine, Hammersmith Hospital London, UK.
authors.forename: S F
authors.initials: SF
authors.lastname: Ahmed
authors.forename: P H
authors.initials: PH
authors.lastname: Dixon
authors.forename: D T
authors.initials: DT
authors.lastname: Bonthron
authors.forename: H F
authors.initials: HF
authors.lastname: Stirling
authors.forename: D G
authors.initials: DG
authors.lastname: Barr
authors.forename: C J
authors.initials: CJ
authors.lastname: Kelnar
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D020033:Protein Isoforms; D011547:Pseudohypoparathyroidism / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D004247:DNA; D019205:GTP-Binding Protein alpha Subunits, Gs