title: A novel deletion in the GH1 gene including the IVS3 branch site responsible for autosomal dominant isolated growth hormone deficiency.
abstract: BACKGROUND
  The majority of mutations responsible for isolated GH type II deficiency (IGHD II) lead to dominant negative deleteriously increased levels of the GH1 exon 3 skipped transcripts.
  
  
  OBJECTIVE
  The aim of this study was the characterization of the molecular defect causing a familial case of IGHD II.
  
  
  METHODS
  A 2-yr-old child and her mother with severe growth failure at diagnosis (-5.8 and -6.9 sd score, respectively) and IGHD were investigated for the presence of GH1 mutations.
  
  
  RESULTS
  We identified a novel 22-bp deletion in IVS3 (IVS3 del+56-77) removing the putative branch point sequence (BPS). Analysis of patients' lymphocyte mRNA showed an excess exon 3 skipping. The mutated allele transfected into rat pituitary cells produced four differently spliced products: the exon 3 skipped mRNA as the main product and lower amounts of the full-length cDNA and of two novel mRNA aberrant isoforms, one with the first 86 bases of exon 4 deleted and the other lacking the entire exon 4. A mutagenized construct lacking exclusively the 7 bp of the BPS only generated the exon 4 skipped and the full-length isoforms. The presence of the full-length transcript in the absence of the canonical BPS points to an alternative BPS in IVS3.
  
  
  CONCLUSIONS
  The IVS3 del+56-77 mutation, causing IGHD II in this family, has two separate effects on mRNA processing: 1) exon 3 skipping, analogous to most described cases of IGHD II, an effect likely caused by the reduction in size of the IVS3, and 2) partial or total exon 4 skipping, as a result of the removal of the BPS.
authors.affiliation: Dipartimento di Scienze Mediche, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vivenza
authors.forename: Laura
authors.initials: L
authors.lastname: Guazzarotti
authors.forename: Michela
authors.initials: M
authors.lastname: Godi
authors.forename: Daniela
authors.initials: D
authors.lastname: Frasca
authors.forename: Berardo
authors.initials: B
authors.lastname: di Natale
authors.forename: Patricia
authors.initials: P
authors.lastname: Momigliano-Richiardi
authors.forename: Gianni
authors.initials: G
authors.lastname: Bona
authors.forename: Mara
authors.initials: M
authors.lastname: Giordano
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D005091:Exons; D005260:Female; D005799:Genes, Dominant; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009035:Mothers; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D019382:Human Growth Hormone