The Growth Hormone Receptor (GHR) c.899dupC Mutation Functions as a Dominant Negative: Insights into the Pathophysiology of Intracellular GHR Defects

摘要

Context:GH insensitivity (GHI) is a condition characterized by pronounced IGF-I deficiency and severe short stature. We previously identified a novel compound heterozygous GH receptor ( GHR ) mutation, GHR:p.R229H/ c.899dupC , in a patient presenting with GHI. The heterozygous p.R229H (prepeptide) variant was previously associated with GHI despite a lack of adequate functional studies. The novel heterozygous GHR: c.899dupC variant affects the critical JAK2-binding Box 1 region of the GHR intracellular domain; the duplication predicted a frameshift and early protein termination.