Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency.
Authors
Petkovic, ViborLochmatter, Didier
Turton, James P
Clayton, Peter E
Trainer, Peter J
Dattani, Mehul T
Eblé, Andrée
Robinson, Iain C
Flück, Christa E
Mullis, Primus E
Affiliation
Department of Pediatric Endocrinology, Diabetology, and Metabolism, Inselspital, University Children's Hospital, CH-3010 Bern, Switzerland.Issue Date
2007-11
Metadata
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CONTEXT AND OBJECTIVE: Alteration of exon splice enhancers (ESE) may cause autosomal dominant GH deficiency (IGHD II). Disruption analysis of a (GAA) (n) ESE motif within exon 3 by introducing single-base mutations has shown that single nucleotide mutations within ESE1 affect pre-mRNA splicing. DESIGN, SETTING, AND PATIENTS: Confirming the laboratory-derived data, a heterozygous splice enhancer mutation in exon 3 (exon 3 + 2 A-->C) coding for GH-E32A mutation of the GH-1 gene was found in two independent pedigrees, causing familial IGHD II. Because different ESE mutations have a variable impact on splicing of exon 3 of GH and therefore on the expression of the 17.5-kDa GH mutant form, the GH-E32A was studied at the cellular level. INTERVENTIONS AND RESULTS: The splicing of GH-E32A, assessed at the protein level, produced significantly increased amounts of 17.5-kDa GH isoform (55% of total GH protein) when compared with the wt-GH. AtT-20 cells coexpressing both wt-GH and GH-E32A presented a significant reduction in cell proliferation as well as GH production after forskolin stimulation when compared with the cells expressing wt-GH. These results were complemented with confocal microscopy analysis, which revealed a significant reduction of the GH-E32A-derived isoform colocalized with secretory granules, compared with wt-GH. CONCLUSION: GH-E32A mutation found within ESE1 weakens recognition of exon 3 directly, and therefore, an increased production of the exon 3-skipped 17.5-kDa GH isoform in relation to the 22-kDa, wt-GH isoform was found. The GH-E32A mutant altered stimulated GH production as well as cell proliferation, causing IGHD II.Citation
Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency. 2007, 92 (11):4427-35 J. Clin. Endocrinol. Metab.Journal
The Journal of Clinical Endocrinology and MetabolismDOI
10.1210/jc.2007-0857PubMed ID
17726075Type
ArticleLanguage
enISSN
0021-972Xae974a485f413a2113503eed53cd6c53
10.1210/jc.2007-0857
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