Targeting GH-1 splicing as a novel pharmacological strategy for growth hormone deficiency type II.

Miletta, Maria Consolata; Flück, Christa Emma; Mullis, Primus-Eugen (2017). Targeting GH-1 splicing as a novel pharmacological strategy for growth hormone deficiency type II. Biochemical pharmacology, 124, pp. 1-9. Elsevier 10.1016/j.bcp.2016.07.016

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Isolated growth hormone deficiency type II (IGHD II) is a rare genetic splicing disorder characterized by reduced growth hormone (GH) secretion and short stature. It is mainly caused by autosomal dominant-negative mutations within the growth hormone gene (GH-1) which results in missplicing at the mRNA level and the subsequent loss of exon 3, producing the 17.5-kDa GH isoform: a mutant and inactive GH protein that reduces the stability and the secretion of the 22-kDa GH isoform, the main biologically active GH form. At present, patients suffering from IGHD II are treated with daily injections of recombinant human GH (rhGH) in order to reach normal height. However, this type of replacement therapy, although effective in terms of growth, does not prevent the toxic effects of the 17.5-kDa mutant on the pituitary gland, which may eventually lead to other hormonal deficiencies. As the severity of the disease inversely correlates with the 17.5-kDa/22-kDa ratio, increasing the inclusion of exon 3 is expected to ameliorate disease symptoms. This review focuses on the recent advances in experimental and therapeutic strategies applicable to treat IGHD II in clinical and preclinical contexts. Several avenues for alternative IGHD II therapy will be discussed including the use of small interfering RNA (siRNA) and short hairpin RNA (shRNA) constructs that specifically target the exon 3-deleted transcripts as well as the application of histone deacetylase inhibitors (HDACi) and antisense oligonucleotides (AONs) to enhance full-length GH-1 transcription, correct GH-1 exon 3 splicing and manipulate GH pathway.

Item Type:

Journal Article (Review Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Endokrinologie / Diabetologie / Metabolik (Pädiatrie)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Endokrinologie / Diabetologie (Erwachsene)

UniBE Contributor:

Miletta, Maria Consolata, Flück Pandey, Christa Emma, Mullis, Primus-Eugen

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0006-2952

Publisher:

Elsevier

Language:

English

Submitter:

Anette van Dorland

Date Deposited:

19 Jul 2017 13:59

Last Modified:

02 Mar 2023 23:29

Publisher DOI:

10.1016/j.bcp.2016.07.016

PubMed ID:

27457999

Uncontrolled Keywords:

GH-1 gene; Growth hormone; Growth hormone deficiency type II; Short stature; Splicing modulation

BORIS DOI:

10.7892/boris.95634

URI:

https://boris.unibe.ch/id/eprint/95634

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