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Endocrine Abstracts (2018) 59 CC5 | DOI: 10.1530/endoabs.59.CC5

1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University London, London, UK; 2Department of Woman, Child, General and Specialized Surgery at Università egli Studi della Campania ‘L. Vanvitelli’, Naples, Italy.

Background: GH Insensitivity (GHI) is usually caused by mutations in the GH receptor (GHR). Our centre previously described the first GHR pseudoexon mutation (42700896A>G, c. 618+792A>G). Inclusion of this 108bp pseudoexon is predicted to lead to in-frame insertion of 36 amino acid residues in the dimerization domain of the GHR. This results in defective trafficking rather than impaired signalling, causing partial loss-of-function and moderate postnatal growth failure (Height SDS −3.3 to −6.0).

Objective and hypothesis: Pseudoexons outnumber exons by 10–1 and variants in them may be a major contributor to disease burden in short stature.

Methods: We designed a custom short stature gene panel that interrogates both coding and non-coding regions. In vitro splicing assays were performed using an exon trap vector (pET01, MoBiTec GmbH, Germany).

Results: We identified a homozygous GHR variant (g.5:42700940T>G, c.618+836T>G) in an Italian patient with severe postnatal growth failure (Height SDS −7.5) and classical Laron phenotype. Both unaffected, non-consanguineous parents were heterozygous for the mutation. This mutation was 44bp downstream of the previous pseudoexon mutation and predicted in silico to create a donor splice site. Splicing analysis confirmed inclusion of the 152bp mutant pseudoexon in all transcripts with no evidence of normal splicing in contrast to the wild-type pseudoexon which showed no such inclusion. Inclusion of the pseudoexon will lead to a frameshift and premature truncation of the mRNA.

Discussion: This novel pseudoexon inclusion event will result in a truncated message which is likely destroyed by nonsense mediated mRNA decay, in keeping with the patient’s undetectable GHBP levels. This will lead to complete loss of function, consistent with the more severe growth failure observed compared to the previously described pseudoexon. Our findings highlight the potential for such splicing events to be more commonly causal for this and other rare diseases.

Volume 59

Society for Endocrinology BES 2018

Glasgow, UK
19 Nov 2018 - 21 Nov 2018

Society for Endocrinology 

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