A novel deletion in the GH1 gene including the IVS3 branch site responsible for autosomal dominant isolated growth hormone deficiency.

Abstract

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 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.

CONCLUSION:

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: Daniela Vivenza, Laura Guazzarotti, Michela Godi, Daniela Frasca, Berardo di Natale, Patricia Momigliano-Richiardi, Gianni Bona, Mara Giordano
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 91 Issue 3 Pg. 980-6 (Mar 2006) ISSN: 0021-972X [Print] United States
• PMID: 16368751 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Human Growth Hormone

Topics

• Base Sequence
• Child, Preschool
• Exons
• Female
• Genes, Dominant
• Human Growth Hormone (deficiency, genetics)
• Humans
• Male
• Molecular Sequence Data
• Mothers
• Pedigree
• Polymerase Chain Reaction
• Sequence Deletion