title: Mutation analysis of the LH receptor gene in Leydig cell adenoma and hyperplasia and functional and biochemical studies of activating mutations of the LH receptor gene.
abstract: BACKGROUND
  Germline and somatic activating mutations in the LH receptor (LHR) gene have been reported.
  
  
  OBJECTIVE
  Our objective was to perform mutation analysis of the LHR gene of patients with Leydig cell adenoma or hyperplasia. Functional studies were conducted to compare the D578H-LHR mutant with the wild-type (WT)-LHR and the D578G-LHR mutant, a classic cause of testotoxicosis. The three main signal transduction pathways in which LHR is involved were studied.
  
  
  METHODS
  We describe eight male patients with gonadotropin-independent precocious puberty due to Leydig cell adenoma or hyperplasia.
  
  
  RESULTS
  The D578H-LHR mutation was found in the adenoma or nodule with hyperplasia in all but two patients. D578H-LHR displayed a constitutively increased but noninducible production of cAMP, led to a very high production of inositol phosphates, and induced a slight phosphorylation of p44/42 MAPK in the absence of human chorionic gonadotropin. The D578G-LHR showed a response intermediate between WT-LHR and the D578H-LHR. Subcellular localization studies showed that the WT-LHR was almost exclusively located at the cell membrane, whereas the D578H-LHR showed signs of internalization. D578H-LHR was the only receptor to colocalize with early endosomes in the absence of human chorionic gonadotropin.
  
  
  CONCLUSIONS
  Although several LHR mutations have been reported in testotoxicosis, the D578H-LHR mutation, which has been found only as a somatic mutation, appears up until now to be specifically responsible for Leydig cell adenomas. This is reflected by the different activation of the signal transduction pathways, when compared with the WT-LHR or D578G-LHR, which may explain the tumorigenesis in the D578H mutant.
authors.affiliation: Department of Pediatrics, Division of Endocrinology, University Medical Center Groningen, Beatrix Children's Hospital, 9700 RB Groningen, The Netherlands. a.m.boot@bkk.umcg.nl
authors.forename: Annemieke M
authors.initials: AM
authors.lastname: Boot
authors.forename: Serge
authors.initials: S
authors.lastname: Lumbroso
authors.forename: Miriam
authors.initials: M
authors.lastname: Verhoef-Post
authors.forename: Annette
authors.initials: A
authors.lastname: Richter-Unruh
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
authors.forename: Ada
authors.initials: A
authors.lastname: Funaro
authors.forename: Auke
authors.initials: A
authors.lastname: Beishuizen
authors.forename: André
authors.initials: A
authors.lastname: van Marle
authors.forename: Stenvert L S
authors.initials: SL
authors.lastname: Drop
authors.forename: Axel P N
authors.initials: AP
authors.lastname: Themmen
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D006801:Humans; D006965:Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007985:Leydig Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009154:Mutation; D011629:Puberty, Precocious / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011974:Receptors, LH / Q000235:genetics* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D011974:Receptors, LH