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Volume 333:1093-1098 October 26, 1995 Number 17 Next

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ABSTRACT

Background Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein.

Methods We studied 14 children with idiopathic short stature who were selected on the basis of normal GH secretion and low serum concentrations of GH-binding protein. Analysis of single-strand conformation polymorphisms and DNA sequencing were both used to identify mutations in the GH-receptor gene.

Results Mutations in the region of the GH-receptor gene that codes for the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that reduced the affinity of the receptor for GH and a second mutation that may affect a function other than ligand binding. The remaining three children had single mutations in one allele of the gene. One mutation introduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor.

Conclusions Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene.

Source Information

From the Departments of Molecular Biology (A.D.G., S.-M.L.), Endocrine Research (R.C.), Protein Engineering (T.C., J.A.W.), and Medical Affairs (K.M.A., N.G., A.C.R.), Genentech, Inc., South San Francisco, Calif.; and the Research Center for Endocrinology and Metabolism, Department of Internal Medicine, University of Göteborg, Göteborg, Sweden (L.M.S.C.).

Address reprint requests to Dr. Goddard at the Department of Molecular Biology, Genentech, Inc., 460 Point San Bruno Blvd., South San Francisco, CA 94080.

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• Fisker, S., Vahl, N., Jorgensen, J. O. L., Christiansen, J. S., Orskov, H. (1997). Abdominal Fat Determines Growth Hormone-Binding Protein Levels in Healthy Nonobese Adults. J. Clin. Endocrinol. Metab. 82: 123-128 [Abstract] [Full Text]  
• Woods, K. A., Camacho-Hubner, C., Savage, M. O., Clark, A. J.L. (1996). Intrauterine Growth Retardation and Postnatal Growth Failure Associated with Deletion of the Insulin-Like Growth Factor I Gene. NEJM 335: 1363-1367 [Full Text]  
• TRIPPEL, S. B., COUTTS, R. D., EINHORN, T. A., MUNDY, G. R., ROSENFELD, R. G. (1996). Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Growth Factors as Therapeutic Agents*{{dagger}}. JBJS 78: 1272-86 [Full Text]  
• Rosenfeld, R. G. (1995). Broadening the Growth Hormone Insensitivity Syndrome. NEJM 333: 1145-1146 [Full Text]