title: Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas.
abstract: OBJECTIVE
  Germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have recently been described in three families with GH or prolactin-secreting tumors, as well as in a few patients with apparently sporadic somatotropinomas. The aim of the study was to determine the prevalence of AIP mutations in a large cohort of patients with apparently sporadic GH-secreting tumors.
  
  
  METHODS
  One hundred and fifty-four patients were included in a prospective cohort designed to study the genetic predisposition to GH-secreting tumors together with 270 controls.
  
  
  METHODS
  In all these subjects, the entire coding sequence of the AIP gene was screened for germline mutations.
  
  
  RESULTS
  AIP mutations were detected in 5 out of 154 patients (3%): nonsense mutations in exon 4 (p.Lys201X; n = 2) and in exon 6 (p.Arg304X), one deletion in exon 3 (c.404delA; pHis135LeufsX21), and one mutation affecting the splice acceptor site of exon 4 (c.469-2 A > G). The five patients with an AIP mutation were significantly younger (mean age +/- S.D.: 25 +/- 10 vs 43 +/- 14 years, P = 0.005) and three of them presented with gigantism. One missense mutation (p.Arg304Gln) was found in a single patient that was absent in all controls.
  
  
  CONCLUSIONS
  Germline mutations of the AIP gene were found in a small proportion of patients with sporadic pituitary somatotropinomas. This study shows that age and gigantism are simple clinical features which can help to select patients for mutation screening. It also supports the role of AIP in pituitary tumorigenesis.
authors.affiliation: INSERM, U567, 75 Paris, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Cazabat
authors.forename: Rossella
authors.initials: R
authors.lastname: Libè
authors.forename: Karine
authors.initials: K
authors.lastname: Perlemoine
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Laurence
authors.initials: L
authors.lastname: Dupasquier-Fediaevsky
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Eric
authors.initials: E
authors.lastname: Clauser
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Raffin-Sanson
mesh_terms: D000172:Acromegaly / Q000235:genetics*; D000236:Adenoma / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D016022:Case-Control Studies; D018389:Codon, Nonsense / Q000032:analysis; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein