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An exon splice enhancer mutation causes autosomal dominant GH deficiency
Chanda T Moseley1, Primus E Mullis, Melissa A Prince
1Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2578, USA. chanda.moseley@mcmail.vanderbilt.edu
The Journal of Clinical Endocrinology and Metabolism
|February 12, 2002
Summary
A novel mutation in exon 3 (E3+ 5 A-->G) disrupts a critical splice enhancer, causing familial isolated growth hormone deficiency type II (IGHD II) by impairing growth hormone mRNA splicing.
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Familial isolated growth hormone deficiency type II (IGHD II) is a genetic disorder affecting growth.
- Mutations in growth hormone (GH) gene splicing are implicated in some IGHD II cases.
Purpose of the Study:
- To investigate the molecular mechanism of a specific exon 3 mutation (E3+ 5 A-->G) in IGHD II.
- To determine the impact of this mutation on GH mRNA processing and protein function.
Main Methods:
- Identified the E3+ 5 A-->G mutation in an IGHD II family.
- Utilized cell transfection assays with modified GH expression constructs.
- Sequenced resulting GH cDNAs to analyze mRNA splicing patterns.
Main Results:
- The E3+ 5 A-->G mutation disrupts an exon splice enhancer (ESE) motif.
- This disruption impairs the IVS2 3' splice site and leads to partial or complete exon 3 skipping.
- Exon skipping results in altered growth hormone protein sequences, lacking critical amino acid residues.
Conclusions:
- The E3+ 5 A-->G mutation is a causative factor for IGHD II.
- Perturbation of the ESE by this mutation disrupts normal GH mRNA splicing, leading to the observed deficiency.