Article ; Online: A novel GHR intronic variant, c.266+83G>T , activates a cryptic 5' splice site causing severe GHR deficiency and classical GH insensitivity syndrome.
Hormone research in paediatrics
2013 Volume 80, Issue 6, Page(s) 397–405
Abstract: Background/aims: Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulin-like growth factor (IGF-1) deficiency. The extracellular domain of GHR (encoded by exons 2-7 ... ...
| Abstract | Background/aims: Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulin-like growth factor (IGF-1) deficiency. The extracellular domain of GHR (encoded by exons 2-7 of the GHR gene) can be proteolytically cleaved to circulate as GH-binding protein (GHBP). Methods: We evaluated the cause of classical GHI (Laron) phenotypes in 3 siblings. Results: Two brothers (aged 16.5 and 14.9 years) and their half-brother (aged 11.3 years) presented with extreme short stature (height standard deviation score, SDS, of -7.05, -6.34 and -8.02, respectively). The parents were consanguineous and of normal stature. Serum GHBP levels of probands were undetectable and circulating IGF-1 and IGF-binding protein-3 were abnormally low, but GH concentrations were elevated. Molecular analysis of the GHR gene revealed homozygous deletion of exon 3, a common polymorphism, and a novel c.266+83G>T variant within intron 4 which generated a 5' donor splice site. Splicing events from this cryptic 5' donor site resulted in retention of 81 intronic nucleotides in the GHR mRNA. Long-term rhIGF-1 therapy combined with leuprolide depot increased height by +2 to +3 SDS. Conclusion: The c.266+83G>T is the second intronic GHR mutation identified that activates a cryptic 5' donor splice site. The abnormal splicing event led to early protein termination and undetectable serum GHBP concentrations. © 2013 S. Karger AG, Basel. |
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| MeSH term(s) | Adolescent ; Base Sequence ; Child ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Introns/genetics ; Laron Syndrome/drug therapy ; Laron Syndrome/genetics ; Male ; Molecular Sequence Data ; Pedigree ; Polymorphism, Single Nucleotide ; RNA Splice Sites/genetics ; Receptors, Somatotropin/genetics ; Severity of Illness Index ; Siblings |
| Chemical Substances | RNA Splice Sites ; Receptors, Somatotropin ; Insulin-Like Growth Factor I (67763-96-6) |
| Language | English |
| Publishing date | 2013 |
| Publishing country | Switzerland |
| Document type | Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2537278-6 |
| ISSN | 1663-2826 ; 1663-2818 |
| ISSN (online) | 1663-2826 |
| ISSN | 1663-2818 |
| DOI | 10.1159/000355404 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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