Jennifer Danzig1, Dong Li2, Suzanne Jan de Beur3, Michael A Levine1. 1. Division of Endocrinology and Diabetes, and The Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. 2. Center for Applied Genomics, The Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. 3. Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract
CONTEXT: Patients with pseudohypoparathyroidism type 1b (PHP1b) show disordered imprinting of the maternal GNAS allele or paternal uniparental disomy (UPD). Genetic deletions in STX16 or in upstream exons of GNAS are present in many familial but not sporadic cases. OBJECTIVE: Characterization of epigenetic and genetic defects in patients with PHP1b. DESIGN AND PATIENTS: DNA from 84 subjects, including 26 subjects with sporadic PHP1b, 27 affected subjects and 17 unaffected and/or obligate gene carriers from 12 PHP1b families, 11 healthy individuals, and 3 subjects with PHP1a was subjected to quantitative pyrosequencing of GNAS differentially methylated regions (DMRs), microarray analysis, and microsatellite haplotype analysis. SETTING: Academic medical center. MAIN OUTCOME MEASUREMENTS: Molecular pathology of PHP1b. RESULTS: Healthy subjects, unaffected family members and obligate carriers of paternal PHP1b alleles, and subjects with PHP1a showed normal methylation of all DMRs. All PHP1b subjects showed loss of methylation (LOM) at the exon A/B DMR. Affected members of 9 PHP1b kindreds showed LOM only at the exon A/B DMR, which was associated with a 3-kb deletion of STX16 exons 4 through 6 in 7 families and a novel deletion of STX16 and adjacent NEPEPL1 in 1 family. A novel NESP deletion was found in 1 of 2 other families with more extensive methylation defects. One sporadic PHP1b had UPD of 20q, 2 had 3-kb STX16 deletions, and 5 had apparent epigenetic mosaicism. CONCLUSIONS: We found diverse patterns of defective methylation and identified novel or previously known mutations in 9 of 12 PHP1b families.
CONTEXT: Patients with pseudohypoparathyroidism type 1b (PHP1b) show disordered imprinting of the maternal GNAS allele or paternal uniparental disomy (UPD). Genetic deletions in STX16 or in upstream exons of GNAS are present in many familial but not sporadic cases. OBJECTIVE: Characterization of epigenetic and genetic defects in patients with PHP1b. DESIGN AND PATIENTS: DNA from 84 subjects, including 26 subjects with sporadic PHP1b, 27 affected subjects and 17 unaffected and/or obligate gene carriers from 12 PHP1b families, 11 healthy individuals, and 3 subjects with PHP1a was subjected to quantitative pyrosequencing of GNAS differentially methylated regions (DMRs), microarray analysis, and microsatellite haplotype analysis. SETTING: Academic medical center. MAIN OUTCOME MEASUREMENTS: Molecular pathology of PHP1b. RESULTS: Healthy subjects, unaffected family members and obligate carriers of paternal PHP1b alleles, and subjects with PHP1a showed normal methylation of all DMRs. All PHP1b subjects showed loss of methylation (LOM) at the exon A/B DMR. Affected members of 9 PHP1b kindreds showed LOM only at the exon A/B DMR, which was associated with a 3-kb deletion of STX16 exons 4 through 6 in 7 families and a novel deletion of STX16 and adjacent NEPEPL1 in 1 family. A novel NESP deletion was found in 1 of 2 other families with more extensive methylation defects. One sporadic PHP1b had UPD of 20q, 2 had 3-kb STX16 deletions, and 5 had apparent epigenetic mosaicism. CONCLUSIONS: We found diverse patterns of defective methylation and identified novel or previously known mutations in 9 of 12 PHP1b families.
Authors: Murat Bastepe; Leopold F Fröhlich; Agnès Linglart; Hilal S Abu-Zahra; Katsuyoshi Tojo; Leanne M Ward; Harald Jüppner Journal: Nat Genet Date: 2004-12-12 Impact factor: 38.330
Authors: Suzanne M Jan De Beur; Jeffery R O'Connell; Rita Peila; Justin Cho; Zhichao Deng; Stephen Kam; Michael A Levine Journal: J Bone Miner Res Date: 2003-03 Impact factor: 6.741
Authors: Elena Ivanova; Sebastian Canovas; Soledad Garcia-Martínez; Raquel Romar; Jordana S Lopes; Dimitrios Rizos; Maria J Sanchez-Calabuig; Felix Krueger; Simon Andrews; Fernando Perez-Sanz; Gavin Kelsey; Pilar Coy Journal: Clin Epigenetics Date: 2020-05-11 Impact factor: 6.551
Authors: Danny E Miller; Patrick Hanna; Miranda Galey; Monica Reyes; Agnès Linglart; Evan E Eichler; Harald Jüppner Journal: J Bone Miner Res Date: 2022-08-03 Impact factor: 6.390
Authors: Colin P Hawkes; Jamal M Al Jubeh; Dong Li; Susan E Tucker; Tara Rajiyah; Michael A Levine Journal: J Clin Endocrinol Metab Date: 2022-05-17 Impact factor: 6.134
Authors: Zentaro Kiuchi; Monica Reyes; Patrick Hanna; Anu Sharma; Terry DeClue; Robert C Olney; Peter Tebben; Harald Jüppner Journal: J Clin Endocrinol Metab Date: 2022-01-18 Impact factor: 6.134