medwireNews: Researchers have identified two naturally occurring, dominant-negative variants in the growth hormone receptor gene (GHR) that act via the same molecular mechanism and contribute to the nonclassical growth hormone insensitivity (GHI) phenotype.
The variants were discovered in two unrelated male patients with GHI by Helen Storr (Queen Mary University London, UK) and colleagues who say that their findings could offer “a potential therapeutic approach” for patients with this type of mutation.
The first participant was a 16.5-year-old male who presented with short stature (height standard deviation score [SDS] –3.2) and small-for-gestational age (birthweight SDS –2.4), “subtle” dysmorphisms, relative macrocephaly and “borderline” mesomelic shortening of the upper limb, the authors say. His mother was also short (SDS –2.4), and he had a heterozygous GHR variant (c.876-15T>G, rs199960137) identified in intron 8.
The second participant was a 14.6-year-old male who also presented with short stature (SDS –2.7). He had a normal birthweight, no dysmorphic features and no family history of short stature but he carried a heterozygous GHR variant (c.902T>G, p.V301G) in exon 9.
Although the two participants had different phenotypes – the first inherited the GHR variant from his mother and had normal GH binding protein (BP) levels and the second had a de novo mutation with elevated GHBP levels – in vitro splicing assays showed that both variants activated the same cryptic splice acceptor site.
This resulted in abnormal splicing and deletion of 26 base pairs of GHR exon 9. The deletion led to the production of nonfunctional, truncated GHRs that exerted a dominant-negative effect causing impaired GH-induced GHR signalling, the team reports in the European Journal of Endocrinology.
Next, Storr and co-investigators used complementation assays to assess protein–protein interactions in live cells. These assays, along with flow cytometry, showed significantly increased cell surface expression of variant GHR homodimers or mutant:wild-type heterodimers relative to wild-type homodimers.
Further testing revealed greater levels of recombinant human (rh)GH binding to variant GHR homo/heterodimers than to GHR wild-type homodimers as well as sequestration of GH to the mutant GHRs and the cleaved GHBP produced by the mutant receptors.
Together, these molecular mechanisms cause an “additive reduction in the availability of GH to bind and signal through the [wild-type] GHR”, the researchers summarise.
Storr et al note: “This is the first published report of naturally-occurring GHR mutations leading to activation of this known alternative exon 9 splice site and presenting clinically with growth restriction.”
They continue: “There are conceivable limitations of rhIGF1 monotherapy, as the important independent growth-promoting effects of GH are not addressed by this approach.
“This highlights the fundamental need to expand the therapeutic options available for patients with [dominant-negative] GHR variants.”
By Laura Cowen
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