GH Alternative Splicing: Mechanisms and Disease

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Splicing is essential for expression of most genes and alternative splicing is a major source of human proteome diversity. At least 15% of all disease causing point mutations, not counting genomic variants that affect intronic or exonic splicing enhancer or silencer elements derange splicing. Many important diseases including cystic fibrosis and familial breast cancer have been linked to rare genomic variants (mutations) and common polymorphisms that alter splicing to produce abnormal, deleterious protein products. Understanding and correcting aberrant splicing caused by genomic variants could prevent expression of disease causing products and lead to new therapies for many genetic diseases. RNA interference with siRNAs can block expression of isoforms caused by numerous splicing mutations making it an attractive therapeutic agent for many genetic disorders, especially dominant negative diseases. Analysis of growth hormone genes from individuals with GH deficiency shows that aberrant skipping of exon 3 can produce a dominant negative 17.5kD isoform. In previous studies the P.I. found that at least three splicing enhancers are needed to ensure correct exon 3 definition and inclusion. The current work is now focused on determining the mechanisms of splicing enhancer function and how rare or common Growth Hormone 1 variants alter splicing to cause GHD or short stature. They will test new therapies to prevent GHD in mouse models where increased 17.5kD levels block secretion of wild type GH to cause cell death in pituitary somatotrophs. To achieve these goals the P.I, plans the following Specific Aims: 1) Determine how GH1 splicing enhancers activate exon 3 inclusion; 2) Determine if allele specific siRNAs can restore secretion in isolated Growth Hormone Deficiency II; 3) Develop new therapeutic approaches to treat Isolated Growth Hormone Deficiency II and 4) Determine how rare GH1 variants cause GHD and the contribution of common GH1 variations to GHD phenotype and short stature.