A Novel GHR Intronic Variant, c.266+83G %26gt; T, Activates a Cryptic 5 %26apos; Splice Site Causing Severe GHR Deficiency and Classical GH Insensitivity Syndrome

作者：Feigerlova Eva; Swinyard Mike; Derr Michael A; Farnsworth Jeannie; Andrew Shayne F; Rosenfeld Ron G; Hwa Vivian^*

来源：Hormone Research in Paediatrics, 2013, 80(6): 397-405.

DOI：10.1159/000355404

• Growth hormone insensitivity syndrome
• Growth hormone receptor splicing mutation
• Growth hormone receptor deficiency

Background/Aims: Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulinlike 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%26gt; T variant within intron 4 which generated a 5%26apos; donor splice site. Splicing events from this cryptic 5%26apos; 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%26gt; T is the second intronic GHR mutation identified that activates a cryptic 5%26apos; donor splice site. The abnormal splicing event led to early protein termination and undetectable serum GHBP concentrations.

• 出版日期2013