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 novel dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a non-classical 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 co-expressed 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 significant 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.