“…To significantly perturb the IGF-I production so necessary for normal growth, mutations in the intracellular domain of GHR would need to disrupt the availability of all 3 critical tyrosines, Y534, Y566 and Y627, hence preventing, or at least significantly reducing, STAT5b signaling. Indeed, the handful of mutations identified in the intracellular domain of GHR that are clearly implicated in IGFD and GHI, involve significant DNA aberrations – frameshifts due to deletions, duplications [27] or splicing mutations [1,2] – which result in either premature protein truncations that abrogate all the critical tyrosines or destabilize the entire GHR protein structure. The prediction, therefore, would be that a simple homozygous missense mutation, even if within one of the critical tyrosines, would have minimal impact on STAT5b signaling, unless the mutation significantly compromised the structure of the GHR.…”