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

Petkovic, Vibor; Lochmatter, Didier; Turton, James; Clayton, Peter E; Trainer, Peter J; Dattani, Mehul T; Eblé, Andrée; Robinson, Iain C; Flück, Christa E; Mullis, Primus E (2007). Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency. Journal of clinical endocrinology and metabolism, 92(11), pp. 4427-35. Chevy Chase, Md.: Endocrine Society 10.1210/jc.2007-0857

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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.

Item Type:

Journal Article (Further Contribution)


04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Pegiazoglou, Ioannis, Lochmatter, Didier, Flück Pandey, Christa Emma, Mullis, Primus-Eugen






Endocrine Society




Anette van Dorland

Date Deposited:

04 Oct 2013 14:55

Last Modified:

12 Oct 2023 15:58

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PubMed ID:


Web of Science ID:





https://boris.unibe.ch/id/eprint/23410 (FactScience: 41741)

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