title: A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gsα Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B).
abstract: Pseudohypoparathyroidism type Ib (PHP1B) is characterized primarily by resistance to parathyroid hormone (PTH) and thus hypocalcemia and hyperphosphatemia, in most cases without evidence for Albright hereditary osteodystrophy (AHO). PHP1B is associated with epigenetic changes at one or several differentially-methylated regions (DMRs) within GNAS, which encodes the α-subunit of the stimulatory G protein (Gsα) and splice variants thereof. Heterozygous, maternally inherited STX16 or GNAS deletions leading to isolated loss-of-methylation (LOM) at exon A/B alone or at all maternal DMRs are the cause of autosomal dominant PHP1B (AD-PHP1B). In this study, we analyzed three affected individuals, the female proband and her two sons. All three revealed isolated LOM at GNAS exon A/B, whereas the proband's healthy maternal grandmother and uncle showed normal methylation at this locus. Haplotype analysis was consistent with linkage to the STX16/GNAS region, yet no deletion could be identified. Whole-genome sequencing of one of the patients revealed a large heterozygous inversion (1,882,433 bp). The centromeric breakpoint of the inversion is located 7,225 bp downstream of GNAS exon XL, but its DMR showed no methylation abnormality, raising the possibility that the inversion disrupts a regulatory element required only for establishing or maintaining exon A/B methylation. Because our three patients presented phenotypes consistent with PHP1B, and not with PHP1A, the Gsα promoter is probably unaffected by the inversion. Our findings expand the spectrum of genetic mutations that lead to LOM at exon A/B alone and thus biallelic expression of the transcript derived from this alternative first GNAS exon. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital Stockholm, Stockholm, Sweden.
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.affiliation: Endocrine Unit, Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
authors.forename: Pasi I
authors.initials: PI
authors.lastname: Nevalainen
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: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Olta
authors.initials: O
authors.lastname: Tafaj
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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: Rieko
authors.initials: R
authors.lastname: Takatani
authors.affiliation: Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Ala-Houhala
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital Stockholm, Stockholm, Sweden.|Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Eisfeldt
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital Stockholm, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.affiliation: Centre Hospitalier Universitaire de Caen, Department of Genetics, Reference Centre for Rare Disorders of Calcium and Phosphorus Metabolism, Caen, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins / Q000235:genetics*; D025063:Chromosome Disorders / Q000235:genetics*; D007446:Chromosome Inversion; D005091:Exons; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008297:Male; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D051438:Syntaxin 16 / Q000235:genetics
chemical_list: D002864:Chromogranins; C496118:STX16 protein, human; D051438:Syntaxin 16; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: DISORDERS OF CALCIUM/PHOSPHATE METABOLISM; EPIGENETICS; G protein; GNAS; PARATHYROID-RELATED DISORDERS