Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency.

2.50
Hdl Handle:
http://hdl.handle.net/10541/70041
Title:
Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency.
Authors:
Petkovic, Vibor; Lochmatter, Didier; Turton, James P; Clayton, Peter E; Trainer, Peter J; Dattani, Mehul T; Eblé, Andrée; Robinson, Iain C; Flück, Christa E; Mullis, Primus E
Abstract:
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.
Affiliation:
Department of Pediatric Endocrinology, Diabetology, and Metabolism, Inselspital, University Children's Hospital, CH-3010 Bern, Switzerland.
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 Metabolism
Issue Date:
Nov-2007
URI:
http://hdl.handle.net/10541/70041
DOI:
10.1210/jc.2007-0857
PubMed ID:
17726075
Type:
Article
Language:
en
ISSN:
0021-972X
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorPetkovic, Vibor-
dc.contributor.authorLochmatter, Didier-
dc.contributor.authorTurton, James P-
dc.contributor.authorClayton, Peter E-
dc.contributor.authorTrainer, Peter J-
dc.contributor.authorDattani, Mehul T-
dc.contributor.authorEblé, Andrée-
dc.contributor.authorRobinson, Iain C-
dc.contributor.authorFlück, Christa E-
dc.contributor.authorMullis, Primus E-
dc.date.accessioned2009-06-09T16:44:02Z-
dc.date.available2009-06-09T16:44:02Z-
dc.date.issued2007-11-
dc.identifier.citationExon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency. 2007, 92 (11):4427-35 J. Clin. Endocrinol. Metab.en
dc.identifier.issn0021-972X-
dc.identifier.pmid17726075-
dc.identifier.doi10.1210/jc.2007-0857-
dc.identifier.urihttp://hdl.handle.net/10541/70041-
dc.description.abstractCONTEXT 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.en
dc.language.isoenen
dc.subject.meshAdolescent-
dc.subject.meshAdult-
dc.subject.meshBlotting, Western-
dc.subject.meshBody Height-
dc.subject.meshCell Proliferation-
dc.subject.meshCell Survival-
dc.subject.meshCells, Cultured-
dc.subject.meshChromosome Disorders-
dc.subject.meshEndoplasmic Reticulum-
dc.subject.meshExons-
dc.subject.meshFemale-
dc.subject.meshForskolin-
dc.subject.meshGenes, Dominant-
dc.subject.meshGenetic Vectors-
dc.subject.meshGolgi Apparatus-
dc.subject.meshHuman Growth Hormone-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMicroscopy, Confocal-
dc.subject.meshMutation-
dc.subject.meshPedigree-
dc.subject.meshProtein Isoforms-
dc.subject.meshRNA, Messenger-
dc.subject.meshSecretory Vesicles-
dc.titleExon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pediatric Endocrinology, Diabetology, and Metabolism, Inselspital, University Children's Hospital, CH-3010 Bern, Switzerland.en
dc.identifier.journalThe Journal of Clinical Endocrinology and Metabolismen

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