Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency

Abstract Objective To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. Design A 2-year-old girl of height 77.2 cm (− 3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7 ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41 μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81 ng/mL with insulin-induced hypoglycemia, 3.78 ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor ( GHRHR ) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. Results Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2 + 3a > g mutation would lead to aberrant splicing. Conclusions A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.