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Decreased Expression of the GHRH Receptor Gene Due to a Mutation in a Pit-1 Binding Site

Divisions of Endocrinology (R.S., X.F., A.H.) and Pediatric Endocrinology (M.A.L.), and the Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and Department of Pediatrics (P.E.M.), Inselspital, University of Bern, Bern, 3010 Switzerland

Address all correspondence and requests for reprints to: Roberto Salvatori, M.D., Division of Endocrinology, Johns Hopkins University School of Medicine, 1830 East Monument Street, no. 333, Baltimore, Maryland 21287. E-mail: salvator{at}jhmi.edu.

A variety of mutations in the gene encoding the GHRH receptor (GHRHR) that are predicted to alter protein structure or function have been recently described in patients with isolated GH deficiency type IB. In the present report we describe a patient with isolated GH deficiency type IB who was heterozygous for two novel mutations in this gene: a missense mutation in codon 329 that replaces lysine with glutamic acid (K329E) and an AC transversion (position -124) in one of the two sites of the promoter region that binds the pituitary-specific transcription factor Pit-1, which is required for GHRHR expression. Chinese hamster ovary cells that were transfected with a cDNA encoding the K329E GHRHR expressed the receptor but failed to show a cAMP response after treatment with GHRH, confirming the lack of functionality. To test the effect of the AC mutation at position -124 of the promoter, we transfected rat GH3 pituitary cells, which express endogenous Pit-1, with plasmids in which the luciferase reporter gene was under the control of either the wild-type or the mutant promoter. GH3 cells expressing the mutant promoter showed significantly less luciferase activity than cells expressing the wild-type promoter. DNA-binding studies confirmed that the AC base change markedly reduces DNA binding to the Pit-1 protein. These results demonstrate that mutations in the GHRHR are not limited to the coding sequence and that promoter mutations that impair Pit-1 binding can reduce expression of the GHRHR gene.

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