title: Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B).
abstract: Pseudohypoparathyroidism type Ib (PHP1B) is caused by proximal tubular resistance to parathyroid hormone that occurs in most cases in the absence of Albright's Hereditary Osteodystrophy (AHO). Familial forms of PHP1B are caused by maternally inherited microdeletions within STX16, the gene encoding syntaxin 16, or within GNAS, a complex genetic locus on chromosome 20q13.3 encoding Gsα and several splice variants thereof. These deletions lead either to a loss-of-methylation affecting GNAS exon A/B alone or to epigenetic changes involving multiple differentially methylated regions (DMRs) within GNAS. Broad GNAS methylation abnormalities are also observed in most sporadic PHP1B (sporPHP1B) cases. However, with the exception of paternal uniparental disomy involving chromosome 20q (patUPD20q), the molecular mechanism leading to this disease variant remains unknown. We now investigated 23 Japanese sporPHP1B cases, who presented with hypocalcemia, hyperphosphatemia, elevated PTH levels, and occasionally with TSH elevations and mild AHO features. Age at diagnosis was 10.6 ± 1.45 years. Calcium, phosphate, and PTH were 6.3 ± 0.23 mg/dL, 7.7 ± 0.33 mg/dL, and 305 ± 34.5 pg/mL, respectively, i.e. laboratory findings that are indistinguishable from those previously observed for Caucasian sporPHP1B cases. All investigated patients showed broad GNAS methylation changes. Eleven individuals were homozygous for SNPs within exon NESP and a pentanucleotide repeat in exon A/B. Two of these patients furthermore revealed homozygosity for numerous microsatellite markers on chromosome 20q raising the possibility of patUPD20q, which was confirmed through the analysis of parental DNA. Based on this and our previous reports, paternal duplication of the chromosomal region comprising the GNAS locus appears to be a fairly common cause of sporPHP1B that is likely to occur with equal frequency in Caucasians and Asians.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Takatani
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Endocrinology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Minagawa
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, University Hospital of Pisa, Pisa, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Molinaro
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Reyes
authors.affiliation: Department of Pediatrics, Kimitsu Chuo Hospital, Kisarazu, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Takatani
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Endocrinology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: Itsuro
authors.initials: I
authors.lastname: Kazukawa
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Nagatsuma
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kashimada
authors.affiliation: Department of Medical Technology and Sciences, International University of Health and Welfare, Fukuoka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Molecular Diagnosis & Division of Clinical Genetics and Proteomics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Department of Molecular Diagnosis & Division of Clinical Genetics and Proteomics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: hjueppner@partners.org.
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D015139:Blotting, Southern; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D024182:Uniparental Disomy / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Epigenetic; GNAS; Parathyroid hormone; Pseudohypoparathyroidism; Uniparental disomy