Anne-Claire Bréhin1, Cindy Colson, Stéphanie Maupetit-Méhouas, Virginie Grybek, Nicolas Richard, Agnès Linglart, Marie-Laure Kottler, Harald Jüppner. 1. Department of Genetics (A.-C.B., C.C., N.R., M.-L.K.), Centre Hospitalier Universitaire de Caen, Reference Centre for Rare Disorders of Calcium and Phosphorus Metabolism, F-14000 Caen, France; Paediatric Endocrinology and Diabetology (S.M.-M., V.G., A.L.), Reference Centre for Rare Disorders of the Mineral Metabolism, AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre 94270, France; Faculté de Médecine, Université Paris Sud, le Kremlin-Bicêtre 94270, France; and Pediatric Nephrology Unit and Endocrine Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
Abstract
CONTEXT: GNAS is one of few genetic loci that undergo allelic-specific methylation resulting in the parent-specific expression of at least four different transcripts. Due to monoallelic expression, heterozygous GNAS mutations affecting either paternally or maternally derived transcripts cause different forms of pseudohypoparathyroidism (PHP), including autosomal-dominant PHP type Ib (AD-PHP1B) associated with loss of methylation (LOM) at exon A/B alone or sporadic PHP1B (sporPHP1B) associated with broad GNAS methylation changes. Similar to effects other imprinted genes have on early development, we recently observed severe intrauterine growth retardation in newborns, later diagnosed with pseudopseudohypoparathyroidism (PPHP) because of paternal GNAS loss-of-function mutations. OBJECTIVES: This study aimed to determine whether GNAS methylation abnormalities affect intrauterine growth. PATIENTS AND METHODS: Birth parameters were collected of patients who later developed sporPHP1B or AD-PHP1B, and of their healthy siblings. Comparisons were made to newborns affected by PPHP or PHP1A. RESULTS: As newborns, AD-PHP1B patients were bigger than their healthy siblings and well above the reference average; increased sizes were particularly evident if the mothers were unaffected carriers of STX16 deletions. SporPHP1B newborns were slightly above average for weight and length, but their overgrowth was less pronounced than that of AD-PHP1B newborns from unaffected mothers. CONCLUSION: LOM at GNAS exon A/B due to maternal STX16 deletions and the resulting biallelic A/B expression are associated with enhanced fetal growth. These findings are distinctly different from those of PPHP patients with paternal GNAS exons 2-13 mutations, whose birth parameters are almost 4.5 z-scores below those of AD-PHP1B patients born to healthy mothers.
CONTEXT: GNAS is one of few genetic loci that undergo allelic-specific methylation resulting in the parent-specific expression of at least four different transcripts. Due to monoallelic expression, heterozygous GNAS mutations affecting either paternally or maternally derived transcripts cause different forms of pseudohypoparathyroidism (PHP), including autosomal-dominant PHP type Ib (AD-PHP1B) associated with loss of methylation (LOM) at exon A/B alone or sporadic PHP1B (sporPHP1B) associated with broad GNAS methylation changes. Similar to effects other imprinted genes have on early development, we recently observed severe intrauterine growth retardation in newborns, later diagnosed with pseudopseudohypoparathyroidism (PPHP) because of paternal GNAS loss-of-function mutations. OBJECTIVES: This study aimed to determine whether GNAS methylation abnormalities affect intrauterine growth. PATIENTS AND METHODS: Birth parameters were collected of patients who later developed sporPHP1B or AD-PHP1B, and of their healthy siblings. Comparisons were made to newborns affected by PPHP or PHP1A. RESULTS: As newborns, AD-PHP1B patients were bigger than their healthy siblings and well above the reference average; increased sizes were particularly evident if the mothers were unaffected carriers of STX16 deletions. SporPHP1B newborns were slightly above average for weight and length, but their overgrowth was less pronounced than that of AD-PHP1B newborns from unaffected mothers. CONCLUSION: LOM at GNAS exon A/B due to maternal STX16 deletions and the resulting biallelic A/B expression are associated with enhanced fetal growth. These findings are distinctly different from those of PPHP patients with paternal GNAS exons 2-13 mutations, whose birth parameters are almost 4.5 z-scores below those of AD-PHP1B patients born to healthy mothers.
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: Murat Bastepe; Leopold F Fröhlich; Geoffrey N Hendy; Olafur S Indridason; Robert G Josse; Hiroyuki Koshiyama; Jarmo Körkkö; Jon M Nakamoto; Arlan L Rosenbloom; Arnold H Slyper; Toshitsugu Sugimoto; Agathocles Tsatsoulis; John D Crawford; Harald Jüppner Journal: J Clin Invest Date: 2003-10 Impact factor: 14.808
Authors: Giovanna Mantovani; Murat Bastepe; David Monk; Luisa de Sanctis; Susanne Thiele; Alessia Usardi; S Faisal Ahmed; Roberto Bufo; Timothée Choplin; Gianpaolo De Filippo; Guillemette Devernois; Thomas Eggermann; Francesca M Elli; Kathleen Freson; Aurora García Ramirez; Emily L Germain-Lee; Lionel Groussin; Neveen Hamdy; Patrick Hanna; Olaf Hiort; Harald Jüppner; Peter Kamenický; Nina Knight; Marie-Laure Kottler; Elvire Le Norcy; Beatriz Lecumberri; Michael A Levine; Outi Mäkitie; Regina Martin; Gabriel Ángel Martos-Moreno; Masanori Minagawa; Philip Murray; Arrate Pereda; Robert Pignolo; Lars Rejnmark; Rebecca Rodado; Anya Rothenbuhler; Vrinda Saraff; Ashley H Shoemaker; Eileen M Shore; Caroline Silve; Serap Turan; Philip Woods; M Carola Zillikens; Guiomar Perez de Nanclares; Agnès Linglart Journal: Nat Rev Endocrinol Date: 2018-08 Impact factor: 43.330