title: A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II.
abstract: BACKGROUND
  Dominant-negative 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. The basis of the variable expression and progression of IGHD II among relatives who share the same GH1 mutation is poorly understood.
  
  
  OBJECTIVE
  We hypothesized that the cellular ratios of mutant/normal GH1 transcripts would correlate with the severity of the IGHD II phenotype. We determined the relative amounts of mutant and normal GH1 transcripts in cell lines and correlated transcript ratios with severity.
  
  
  METHODS
  Members of the same IGHD II kindred were genotyped for the GH1 E3+1 G/A mutation by DNA sequencing. Ratios of their 17.5-kDa (mutant)/22-kDa (normal) GH1 transcripts were determined in cultured lymphocytes (CLs), and these ratios were correlated with height sd scores obtained before GH replacement therapy.
  
  
  RESULTS
  Ratios of 17.5-/22-kDa GH1 transcripts in CLs from family members with the same IGHD II mutation correlated with differences in their height SD scores.
  
  
  CONCLUSIONS
  Our findings suggest that expression levels of both the mutant and normal GH1 allele are important in the pathogenesis of IGHD II, that the ratio of mutant/normal transcripts may be a predictive marker of the penetrance and severity of IGHD II, and that CLs may be useful as surrogates to study GH1 transcript expression of subjects whose anterior pituitary cells are not available.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2578, USA. Rizwan.Hamid@vanderbilt.edu
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Cindy
authors.initials: C
authors.lastname: Holladay
authors.forename: Joy D
authors.initials: JD
authors.lastname: Cogan
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.forename: Philippe F
authors.initials: PF
authors.lastname: Backeljauw
authors.forename: Sharon H
authors.initials: SH
authors.lastname: Travers
authors.forename: James G
authors.initials: JG
authors.lastname: Patton
mesh_terms: D000483:Alleles; D002460:Cell Line; D004247:DNA / Q000032:analysis / Q000235:genetics; D004393:Dwarfism, Pituitary / Q000235:genetics*; D005091:Exons; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D005819:Genetic Markers; D019382:Human Growth Hormone; D004247:DNA