title: Complex Genomic Rearrangement Within the GNAS Region Associated With Familial Pseudohypoparathyroidism Type 1b.
abstract: Pseudohypoparathyroidism type 1b (PHP-1b) results from methylation defects at the G protein stimulatory α subunit (GNAS) exon A/B-differentially methylated region (DMR). Although microduplications in the GNAS region were recently identified in two PHP-1b patients, genetic information on these patients remained fragmentary.
  
  
  
  A 20-year-old Japanese male and his mother presented with hypocalcemia and elevated blood levels of intact PTH. The proband had a maternal uncle who was previously diagnosed with PHP-1b. Methylation-specific multiplex ligation-dependent probe amplification, array-based comparative genomic hybridization, pyrosequencing, fluorescence in situ hybridization, and whole-genome sequencing were performed for this family. The proband, mother, and uncle carried maternally derived approximately 133-kb duplication-triplication-duplication rearrangements at 20q13.32 involving NESP55, NESPAS, XLαs, and exon A/B-DMR but not STX16 or the Gsα coding region. These individuals exhibited partial methylation defects of NESP55-, NESPAS-, and XLαs-DMRs, which were ascribable to the increased copy numbers of these regions retaining the maternally derived methylation pattern and loss of methylation of exon A/B-DMR, which was inexplicable by the copy-number alterations. Fusion junctions of the rearrangement resided within non-repeat sequences and were accompanied by short-templated insertions.
  
  
  
  Our results indicate that maternally derived copy-number gains in the GNAS region mediated by nonhomologous end-joining and/or by break-induced replication can underlie autosomal dominant PHP-1b. These rearrangements likely affect methylation of exon A/B-DMR by disconnecting or disrupting its cis-acting regulator(s). This study provides a novel example of human disorders resulting from functional disturbance in the cis-regulatory machinery of DNA methylation.
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Hamaguchi
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sano
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagasaki
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Kagami
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Okamura
authors.affiliation: Departments of Molecular Endocrinology (A.N., K.M., S.S., M.K., M.F.) and Systems BioMedicine (K.O.) and Institute (Y.M.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Division of Endocrinology and Metabolism (R.H.), National Medical Center for Children and Mothers, Tokyo 157-8535, Japan; Department of Internal Medicine (E.H., Y.N.), Japanese Red Cross Kanazawa Hospital, Kanazawa 921-8162, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development (K.N.), Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Department of Reproductive Biology (A.U.), Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics (T.T.), Jichi Children's Medical Center Tochigi, Shimotsuke 329-0498, Japan; and Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
mesh_terms: D000328:Adult; D002864:Chromogranins / Q000235:genetics*; D002869:Chromosome Aberrations; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D009035:Mothers; D009679:Nuclear Family; D011547:Pseudohypoparathyroidism / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs