ArticleHuman genetics2003
Disruption of exon definition produces a dominant-negative growth hormone isoform that causes somatotroph death and IGHD II.
Article in Human genetics, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 62 citations in OpenAlex.
- Common and Uncommon Mouse Models of Growth Hormone Deficiency.Endocrine reviews · 2024Review
- Phenotype-Genotype Correlations of GH1 Gene Variants in Patients with Isolated Growth Hormone Deficiency or Multiple Pituitary Hormone Deficiency.Hormone research in paediatrics · 2024Article
- Phenotype-genotype correlations in congenital isolated growth hormone deficiency (IGHD).Indian journal of pediatrics · 2012Review
- Pharmacologic correction of dominant-negative GH1 deficiency causing mutations.Clinical and translational science · 2011Article
- Characterizing ncRNAs in Human Pathogenic Protists Using High-Throughput Sequencing Technology.Frontiers in genetics · 2011Article
- Genetic causes and treatment of isolated growth hormone deficiency-an update.Nature reviews. Endocrinology · 2010Review
- Transposable elements in disease-associated cryptic exons.Human genetics · 2010Article
- Genetics of isolated growth hormone deficiency.Journal of clinical research in pediatric endocrinology · 2010Review
- A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II.The Journal of clinical endocrinology and metabolism · 2009Article
- Isolated growth hormone deficiency type II caused by a point mutation that alters both splice site strength and splicing enhancer function.Clinical genetics · 2008Article
- Growth hormone deficiency and splicing fidelity: two serine/arginine-rich proteins, ASF/SF2 and SC35, act antagonistically.The Journal of biological chemistry · 2008Article
- Rescue of pituitary function in a mouse model of isolated growth hormone deficiency type II by RNA interference.Endocrinology · 2008Article
- Human growth hormone (GH1) gene polymorphism map in a normal-statured adult population.Clinical endocrinology · 2007Article
- Dominant-negative diabetes insipidus and other endocrinopathies.The Journal of clinical investigation · 2003Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Isolated growth hormone deficiency type II (IGHD II) is characterized by short stature due to dominant-negative mutations of the human growth hormone gene (GH1). Most of the known mutations responsible for IGHD II cause aberrant splicing of GH1 transcripts. We have recently shown that mutations that cause exon 3 skipping and produce a dominant-negative 17.5-kDa isoform in humans also cause a dose-dependent disruption of GH secretory vesicles when expressed in GC cells and transgenic mice. We show here that overexpression of the dominant-negative 17.5-kDa isoform also destroys the majority of somatotrophs, leading to anterior pituitary hypoplasia in transgenic mice. It is, therefore, important to understand the regulation of GH1 splicing and why its perturbation causes IGHD II. We demonstrate that dual splicing enhancers are required to ensure exon 3 definition to produce full-length 22-kDa hormone. We also show that splicing enhancer mutations that weaken exon 3 recognition produce variable amounts of the 17.5-kDa isoform, a result which could potentially explain the clinical variability observed in IGHD II. Non-canonical splicing mutations that disrupt splicing enhancers, such as those illustrated here, demonstrate the importance of enhancer elements in regulating alternative splicing to prevent human disease.
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