A Novel Deletion in the GH1 Gene Including the IVS3 Branch Site Responsible for Autosomal Dominant Isolated Growth Hormone Deficiency

Context: 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. Patients: 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...