title: Pharmacologic correction of dominant-negative GH1 deficiency causing mutations.
abstract: OBJECTIVE
  Dominant-negative growth hormone gene (GH1) mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. We have previously shown that 17.5-/22-kDa GH1 transcript ratios correlate with the severity of the IGHD II phenotype. We hypothesized that different pharmaceutical agents could affect the GH1 transcript ratio by modulating alternative splicing.
  
  
  METHODS
  We exposed peripheral blood mononuclear cells from IGHD II patients and unaffected family members to different pharmacologic agents and then determined the 17.5-/22-kDa transcript ratios by real-time PCR.
  
  
  RESULTS
  Dexamethasone and digoxin significantly increased the 17.5-/22-kDa transcript ratio, while sodium butyrate and 5-iodotubericidin significantly decreased the ratio.
  
  
  CONCLUSIONS
  Since we have previously shown that the ratio of the 17.5-/22-kDa GH1 transcripts correlates with severity of the IGHD II phenotype, our findings here suggest that selected previously unconsidered agents could possibly reduce the severity of IGHD II, while other agents could possibly exacerbate the disease phenotype.
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: Justin S
authors.initials: JS
authors.lastname: Poling
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Joy D
authors.initials: JD
authors.lastname: Cogan
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
mesh_terms: D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology; D005192:Family Health; D005799:Genes, Dominant; D013006:Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D009154:Mutation; D010641:Phenotype; D010900:Pituitary Diseases / Q000188:drug therapy* / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012978:Sodium Oxybate / Q000494:pharmacology; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; C034214:5-iodotubercidin; D004077:Digoxin; D012978:Sodium Oxybate; D003907:Dexamethasone; D013006:Growth Hormone; D014372:Tubercidin