Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency

Abstract

Context:Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype.Objective:To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients.Results:All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation.Conclusion:Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.

Severe growth failure associated with a novel heterozygous nonsense mutation in the GHR transmembrane domain leading to elevated growth hormone binding protein

“…This is comparable to previous reports, 8,11,15,19 and consistent with the clinical heterogeneity of patients with dominant-negative mutations in GHR. 9 Both the patient and his mother, moreover, had normal or slightly elevated levels of IGF-1. Although the aetiology of the mother's elevated IGF-1 is presently unknown, the implication is that circulating IGF-1 levels may not always accurately reflect GH action in vivo.…”

“…We recommend evaluation of serum GHBP in cases where the measured serum GH, IGF‐1 and IGFBP‐3 are uncharacteristically normal. Optimal therapy in cases of elevated GHBP associated with nonclassical GHI and short stature could include higher rhGH dosing, with or without rhIGF‐1, as has been demonstrated for other dominant‐negative GHR mutations …”

“…To date, there have only been seven dominant-negative, heterozygous GHR mutations described though there are likely many undiagnosed cases. 9 Importantly, patients with dominant-negative mutations may present with milder phenotypes compared to patients with classical homozygous autosomal-recessive GHI, and therefore be characterized as having idiopathic short stature or may be missed during routine clinical work. A robust GH stimulation test in the background of normal IGF-1 can be an important clue of a nonclassical GHI phenotype, as it was for our present case.…”

“…Biochemically, LS classically presents with low levels of circulating insulin‐like growth factor (IGF)‐1, IGF binding protein (IGFBP)‐3, GH binding protein (GHBP) and acid‐labile subunit (ALS) while circulating GH levels remain normal or even elevated . While cases of classic LS are due to bi‐allelic mutations in the extracellular domain of GHR leading to low levels of GHBP, rare heterozygous mutations of GHR can lead to a dominant‐negative effect resulting in a milder GHI syndrome …”

“…[4][5][6] While cases of classic LS are due to bi-allelic mutations in the extracellular domain of GHR leading to low levels of GHBP, rare heterozygous mutations of GHR can lead to a dominant-negative effect resulting in a milder GHI syndrome. [6][7][8][9][10] Growth hormone (GH) exerts its action via GHR which is encoded on chromosome 5p13.1-12 and consists of 9 introns and 10 exons. Exons 2-7 encode the extracellular portion of GHR, exon 8 is responsible for the transmembrane portion of GHR that anchors the receptor, and exons 9 and 10 encode the intracellular regions of GHR.…”