title: A novel GHR intronic variant, c.266+83G>T , activates a cryptic 5' splice site causing severe GHR deficiency and classical GH insensitivity syndrome.
abstract: OBJECTIVE
  Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulin-like growth factor (IGF-1) deficiency. The extracellular domain of GHR (encoded by exons 2-7 of the GHR gene) can be proteolytically cleaved to circulate as GH-binding protein (GHBP).
  
  
  METHODS
  We evaluated the cause of classical GHI (Laron) phenotypes in 3 siblings.
  
  
  RESULTS
  Two brothers (aged 16.5 and 14.9 years) and their half-brother (aged 11.3 years) presented with extreme short stature (height standard deviation score, SDS, of -7.05, -6.34 and -8.02, respectively). The parents were consanguineous and of normal stature. Serum GHBP levels of probands were undetectable and circulating IGF-1 and IGF-binding protein-3 were abnormally low, but GH concentrations were elevated. Molecular analysis of the GHR gene revealed homozygous deletion of exon 3, a common polymorphism, and a novel c.266+83G>T variant within intron 4 which generated a 5' donor splice site. Splicing events from this cryptic 5' donor site resulted in retention of 81 intronic nucleotides in the GHR mRNA. Long-term rhIGF-1 therapy combined with leuprolide depot increased height by +2 to +3 SDS.
  
  
  CONCLUSIONS
  The c.266+83G>T is the second intronic GHR mutation identified that activates a cryptic 5' donor splice site. The abnormal splicing event led to early protein termination and undetectable serum GHBP concentrations. © 2013 S. Karger AG, Basel.
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, Portland, Oreg., USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Feigerlova
authors.forename: Mike
authors.initials: M
authors.lastname: Swinyard
authors.forename: Michael A
authors.initials: MA
authors.lastname: Derr
authors.forename: Jeannie
authors.initials: J
authors.lastname: Farnsworth
authors.forename: Shayne F
authors.initials: SF
authors.lastname: Andrew
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use; D007438:Introns / Q000235:genetics; D046150:Laron Syndrome / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics*; D011986:Receptors, Somatotropin / Q000235:genetics*; D012720:Severity of Illness Index; D035781:Siblings
chemical_list: D022821:RNA Splice Sites; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I