title: Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism.
abstract: OBJECTIVE
  Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations in the GNAS locus.
  
  
  METHODS
  Investigation of clinical characteristics and molecular analysis in PHP and PPHP.
  
  
  METHODS
  Fourteen subjects from 13 unrelated families including subjects with PPHP (n = 1), PHP-Ia (n = 6) and PHP-Ib (n = 7) were enrolled.
  
  
  METHODS
  Clinical data, including age at presentation, presenting symptom, auxological findings, family history, presence of Albright hereditary osteodystrophy (AHO) features and hormonal and biochemical findings, were analysed. The GNAS locus was subjected to direct sequencing and methylation analysis using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).
  
  
  RESULTS
  Of the 13 PHP subjects, 10 (three PHP-Ia and seven PHP-Ib) presented with hypocalcemic tetany at ages ranging from 7 to 14·8 years. Subcutaneous calcification was observed as an early manifestation of AHO in one PHP-Ia patient (age, 2·9 years) and one PPHP patient (age, 7 months). Six PHP-Ia and one PPHP harboured four different heterozygous mutations within the coding region of GNAS, p.Asp189_Tyr190delinsMetfxX14, p.Val117fsX23, p.Tyr190CysfsX19, and a splicing mutation (c.659 + 1G>A), of which the latter two were novel. Five subjects with PHP-Ib exhibited complete loss of the maternal-specific methylation pattern. The remaining two PHP-Ib showed a loss of methylation of exon 1A on the maternal allele as a consequence of heterozygous 3-kb microdeletions within the STX16 gene.
  
  
  CONCLUSIONS
  GNAS mutation analyses and MS-MLPA assays are useful molecular tools for understanding the molecular bases and confirming the diagnosis of PHP and PPHP.
authors.affiliation: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Jin
authors.forename: Beom Hee
authors.initials: BH
authors.lastname: Lee
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Jin-Kyung
authors.initials: JK
authors.lastname: Kim
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Jeesuk
authors.initials: J
authors.lastname: Yu
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Yoo
authors.forename: Cheol Woo
authors.initials: CW
authors.lastname: Ko
authors.forename: Han-Hyuk
authors.initials: HH
authors.lastname: Lim
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Chung
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011547:Pseudohypoparathyroidism / Q000175:diagnosis / Q000235:genetics*; D011556:Pseudopseudohypoparathyroidism / Q000175:diagnosis / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs