title: PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption.
abstract: BACKGROUND
  Pituitary stalk interruption represents a frequent feature of congenital hypopituitarism, but only rare cases have been assigned to a known genetic cause.
  
  
  OBJECTIVE
  Using a candidate gene approach, we tested several genes as potential causes of hypopituitarism with pituitary stalk interruption. We hypothesized that ectopic posterior pituitary may be a consequence of defective neuronal axon projections along the pituitary stalk or defective angiogenesis of hypophyseal portal circulation. Considering the role of the prokineticin 2 pathway in angiogenesis and neuronal migration, we screened PROK2 and PROKR2 genes.
  
  
  METHODS
  PROK2 and PROKR2 and all genes previously known to be involved in hypopituitarism with pituitary stalk interruption (LHX4, HESX1, OTX2, and SOX3) were screened in 72 index cases with pituitary stalk interruption syndrome from the GENHYPOPIT database. In vitro studies were performed to assess the functional consequences of allelic variants.
  
  
  RESULTS
  We identified two heterozygous PROKR2 mutations (p.Leu173Arg and p.Arg85His) previously reported in isolated hypogonadotroph hypogonadism and a novel PROKR2 variant (p.Ala51Thr) that, in contrast with both other mutations, did not impair receptor signaling activity. Three allelic variants of HESX1 were identified: the heterozygous p.Phe156Ser and the homozygous p.Arg109X mutations were functionally deleterious, whereas p.Ser67Thr was found as a rare allelic variant in association with p.Arg85His PROKR2 mutation in the same patient.
  
  
  CONCLUSIONS
  We report PROKR2 variants in congenital hypopituitarism with pituitary stalk interruption, suggesting a potential role of the prokineticin pathway in pituitary development.
authors.affiliation: Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille (CRN2M), Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7286, Aix-Marseille University, France. rachel.reynaud@ap-hm.fr
authors.forename: Rachel
authors.initials: R
authors.lastname: Reynaud
authors.forename: Sujatha A
authors.initials: SA
authors.lastname: Jayakody
authors.forename: Carine
authors.initials: C
authors.lastname: Monnier
authors.forename: Alexandru
authors.initials: A
authors.lastname: Saveanu
authors.forename: Jérome
authors.initials: J
authors.lastname: Bouligand
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Guedj
authors.forename: Gilbert
authors.initials: G
authors.lastname: Simonin
authors.forename: Pierre
authors.initials: P
authors.lastname: Lecomte
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Philippe
authors.initials: P
authors.lastname: Rondard
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005192:Family Health; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D008297:Male; D009479:Neuropeptides / Q000235:genetics; D010375:Pedigree; D010902:Pituitary Gland / Q000002:abnormalities*; D017354:Point Mutation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide