title: Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89L GH mutation on clinical follow-up and GH secretion.
abstract: OBJECTIVE
  Four distinct familial types of isolated GH deficiency (IGHD) are classified, of which type II, IGHD II, is the autosomal dominant inherited form. Based on clinical data, it became evident that there is a wide variability in phenotype among the various GH-1 gene alterations leading to the disorder. As subjects suffering from IGHD II caused by the specific missense mutated P89L GH (C6129T) have never been reported in detail, the aim was to analyse the impact of this mutated GH form on its clinical follow-up as well as to study its effect at the cellular level in comparison with the most common missense mutation R183H GH (G6664A).
  
  
  METHODS
  Twelve subjects belonging to four families presenting with P89L GH were clinically compared with 17 subjects from 5 families with the R183H GH missense mutation. Further, co-localization of the wild-type (wt-type) and mutant GH forms was studied in AtT-20 cells, mouse pituitary gland, applying quantitative confocal microscopy analysis. Using immunofluorescent techniques, cells were double stained for GH and one of the following organelles: endoplasmic reticulum (anti-Grp94), Golgi (anti-betaCOP) and secretory granules (anti-Rab3a). In addition, GH secretion and cell viability was analysed in detail.
  
  
  RESULTS
  Importantly, as well as growth hormone deficiency, eight out of twelve subjects with the P89L mutated GH form developed other endocrine deficits and the pituitary gland became smaller over time (P < 0.05). At the cellular level, quantitative analysis of the variable mutants expressed in AtT-20 cells revealed a different extent of co-localization, different effects on GH secretion, and, therefore, a different impact on the secretory pathway which might be caused by different folding or aggregation problems necessary for sorting, packaging and/or secretion through the regulated secretory pathway.
  
  
  CONCLUSIONS
  Our results show that specific and detailed analyses of the different mutations identified in IGHD II may shed light on the different mechanisms of secretory pathophysiology, and may provide a better explanation of the range of clinical features associated with GH missense isoforms. Importantly, the findings in patients with P89L GH extend beyond classical IGHD and stress the need for continued clinical vigilance in IGHD II patients for the development of other hormonal deficiencies.
authors.affiliation: Paediatric Endocrinology, University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland.
authors.forename: Souzan
authors.initials: S
authors.lastname: Salemi
authors.forename: Shida
authors.initials: S
authors.lastname: Yousefi
authors.forename: Kurt
authors.initials: K
authors.lastname: Baltensperger
authors.forename: Iain C A F
authors.initials: IC
authors.lastname: Robinson
authors.forename: Andrée
authors.initials: A
authors.lastname: Eblé
authors.forename: Dominique
authors.initials: D
authors.lastname: Simon
authors.forename: Paul
authors.initials: P
authors.lastname: Czernichow
authors.forename: Gerhard
authors.initials: G
authors.lastname: Binder
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sonnet
authors.forename: Primus E
authors.initials: PE
authors.lastname: Mullis
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D005260:Female; D013006:Growth Hormone / Q000378:metabolism; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology*; D010375:Pedigree; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D019382:Human Growth Hormone; D005576:Colforsin; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone