A novel GHR intronic variant, c.266+83G>T , activates a cryptic 5' splice site causing severe GHR deficiency and...

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).

We evaluated the cause of classical GHI (Laron) phenotypes in 3 siblings.

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.

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.