title: Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.
abstract: BACKGROUND
  Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.
  
  
  METHODS
  We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.
  
  
  RESULTS
  We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.
  
  
  CONCLUSIONS
  We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Trivellin
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Daly
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.forename: Liliya
authors.initials: L
authors.lastname: Rostomyan
authors.forename: Darwin O
authors.initials: DO
authors.lastname: Larco
authors.forename: Marie Helene
authors.initials: MH
authors.lastname: Schernthaner-Reiter
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.forename: Letícia F
authors.initials: LF
authors.lastname: Leal
authors.forename: Jean-Hubert
authors.initials: JH
authors.lastname: Caberg
authors.forename: Emilie
authors.initials: E
authors.lastname: Castermans
authors.forename: Chiara
authors.initials: C
authors.lastname: Villa
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Dimopoulos
authors.forename: Prashant
authors.initials: P
authors.lastname: Chittiboina
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.forename: Nalini
authors.initials: N
authors.lastname: Shah
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Lysy
authors.forename: Emanuele
authors.initials: E
authors.lastname: Ferrante
authors.forename: Natalia
authors.initials: N
authors.lastname: Strebkova
authors.forename: Nadia
authors.initials: N
authors.lastname: Mazerkina
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Rodrigo Bertollo
authors.initials: RB
authors.lastname: de Alexandre
authors.forename: Allison D
authors.initials: AD
authors.lastname: Manning
authors.forename: Isaac
authors.initials: I
authors.lastname: Levy
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Keil
authors.forename: Maria de la Luz
authors.initials: Mde L
authors.lastname: Sierra
authors.forename: Leonor
authors.initials: L
authors.lastname: Palmeira
authors.forename: Wouter
authors.initials: W
authors.lastname: Coppieters
authors.forename: Michel
authors.initials: M
authors.lastname: Georges
authors.forename: Luciana A
authors.initials: LA
authors.lastname: Naves
authors.forename: Mauricette
authors.initials: M
authors.lastname: Jamar
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.forename: T John
authors.initials: TJ
authors.lastname: Wu
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Choong
authors.forename: Jerome
authors.initials: J
authors.lastname: Bertherat
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Peter
authors.initials: P
authors.lastname: Kamenický
authors.forename: William E
authors.initials: WE
authors.lastname: Farrell
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: Ivana
authors.initials: I
authors.lastname: Bjelobaba
authors.forename: Stanko S
authors.initials: SS
authors.lastname: Stojilkovic
authors.forename: Jurgen
authors.initials: J
authors.lastname: Wess
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Albert
authors.initials: A
authors.lastname: Beckers
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000172:Acromegaly / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication; D041321:Chromosomes, Human, X; D005260:Female; D005877:Gigantism / Q000235:genetics*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics*
chemical_list: C000594175:GPR101 protein, human; D043562:Receptors, G-Protein-Coupled; D019382:Human Growth Hormone