This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hayashi, Y. Articles by Seo, H. Search for Related Content PubMed PubMed Citation Articles by Hayashi, Y. Articles by Seo, H.

Inhibition of Growth Hormone (GH) Secretion by a Mutant GH-I Gene Product in Neuroendocrine Cells Containing Secretory Granules: An Implication for Isolated GH Deficiency Inherited in an Autosomal Dominant Manner¹

Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine, Nagoya University (Y.H., M.Y., S.O., H.S.), Furo-cho, Chikusa-ku, Nagoya 464-8601; the Department of Pediatrics, Kamiida Daiichi General Hospital (T.K.), Kita-ku, Nagoya 462-0802; and Ogawa Clinic (M.O.), Nagoya 461-0001, Japan

Address all correspondence and requests for reprints to: Yoshitaka Hayashi, M.D. Ph.D., Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: hayashiy{at}endeavor.riem.nagoya-u.ac.jp

Isolated GH deficiency (IGHD) type II is a disease inherited in an autosomal dominant manner. Although point mutations at the donor splice site of intron 3 of the GH-I gene have been identified in patients, the mechanism of how such mutations result in severe GH deficiency is unclear. Recently, we identified two mutations in Japanese patients with IGHD type II, G to A substitutions at the first (mutA) and fifth (mutE) nucleotides of intron 3. Messenger ribonucleic acids skipping exon 3 were transcribed from both mutant GH-I genes. We studied in this report the synthesis and secretion of GH encoded by the mutant GH-I genes and tested whether inhibition of wild-type GH secretion by mutant products could be demonstrated in cultured cell lines.

A metabolic labeling study in COS-1 cells revealed that a mutant GH with a reduced molecular mass was synthesized from the mutant messenger ribonucleic acid and retained in the cells for at least 6 h. On the other hand, the wild-type GH was rapidly secreted into the medium. Coexpression of mutant and wild-type GH did not result in any inhibition of wild-type GH secretion in COS-1 or HepG2 cells. However, coexpression of mutant GH resulted in significant inhibition of wild-type GH secretion in somatotroph-derived MtT/S cells as well as in adrenocorticotroph-derived AtT-20 cells, without affecting cell viability. We conclude that the dominant negative effect of mutant GH on the secretion of wild-type GH is at least in part responsible for the pathogenesis of IGHD type II. Our results also suggest that neuroendocrine cell type-specific mechanisms, including intracellular storage of the secretory proteins, are involved in the inhibition.

This article has been cited by other articles:

				N. Shariat, R. C. C. Ryther, J. A. Phillips III, I. C. A. F. Robinson, and J. G. Patton Rescue of Pituitary Function in a Mouse Model of Isolated Growth Hormone Deficiency Type II by RNA Interference Endocrinology, February 1, 2008; 149(2): 580 - 586. [Abstract] [Full Text] [PDF]

				V. Petkovic, D. Lochmatter, J. Turton, P. E. Clayton, P. J. Trainer, M. T. Dattani, A. Eble, I. C. Robinson, C. E. Fluck, and P. E. Mullis Exon Splice Enhancer Mutation (GH-E32A) Causes Autosomal Dominant Growth Hormone Deficiency J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4427 - 4435. [Abstract] [Full Text] [PDF]

				S. Salemi, S. Yousefi, D. Lochmatter, A. Eble, J. Deladoey, I. C. A. F. Robinson, H.-U. Simon, and P. E. Mullis Isolated Autosomal Dominant Growth Hormone Deficiency: Stimulating Mutant GH-1 Gene Expression Drives GH-1 Splice-Site Selection, Cell Proliferation, and Apoptosis Endocrinology, January 1, 2007; 148(1): 45 - 53. [Abstract] [Full Text] [PDF]

				J. P G Turton, C. R Buchanan, I. C A F Robinson, S. J B Aylwin, and M. T Dattani Evolution of gonadotropin deficiency in a patient with type II autosomal dominant GH deficiency Eur. J. Endocrinol., December 1, 2006; 155(6): 793 - 799. [Abstract] [Full Text] [PDF]

				P. E. Mullis, I. C. A. F. Robinson, S. Salemi, A. Eble, A. Besson, J.-M. Vuissoz, J. Deladoey, D. Simon, P. Czernichow, and G. Binder Isolated Autosomal Dominant Growth Hormone Deficiency: An Evolving Pituitary Deficit? A Multicenter Follow-Up Study J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2089 - 2096. [Abstract] [Full Text] [PDF]

				D. I. Iliev, N. E. Wittekindt, M. B. Ranke, and G. Binder Structural Analysis of Human Growth Hormone with Respect to the Dominant Expression of Growth Hormone (GH) Mutations in Isolated GH Deficiency Type II Endocrinology, March 1, 2005; 146(3): 1411 - 1417. [Abstract] [Full Text] [PDF]

				P. E Mullis Genetic control of growth Eur. J. Endocrinol., January 1, 2005; 152(1): 11 - 31. [Abstract] [Full Text] [PDF]

				R. C. C. Ryther, A. S. Flynt, B. D. Harris, J. A. Phillips III, and J. G. Patton GH1 Splicing Is Regulated by Multiple Enhancers Whose Mutation Produces a Dominant-Negative GH Isoform That Can Be Degraded by Allele-Specific Small Interfering RNA (siRNA) Endocrinology, June 1, 2004; 145(6): 2988 - 2996. [Abstract] [Full Text] [PDF]

				C. W. E. Meyer, D. Korthaus, W. Jagla, E. Cornali, J. Grosse, H. Fuchs, M. Klingenspor, S. Roemheld, M. Tschop, G. Heldmaier, et al. A Novel Missense Mutation in the Mouse Growth Hormone Gene Causes Semidominant Dwarfism, Hyperghrelinemia, and Obesity Endocrinology, May 1, 2004; 145(5): 2531 - 2541. [Abstract] [Full Text] [PDF]

				L. McGuinness, C. Magoulas, A. K. Sesay, K. Mathers, D. Carmignac, J.-B. Manneville, H. Christian, J. A. Phillips III, and I. C. A. F. Robinson Autosomal Dominant Growth Hormone Deficiency Disrupts Secretory Vesicles in Vitro and in Vivo in Transgenic Mice Endocrinology, February 1, 2003; 144(2): 720 - 731. [Abstract] [Full Text] [PDF]

				Y. L. Zhu, B. Conway-Campbell, M. J. Waters, and P. S. Dannies Prolonged Retention after Aggregation into Secretory Granules of Human R183H-Growth Hormone (GH), a Mutant that Causes Autosomal Dominant GH Deficiency Type II Endocrinology, November 1, 2002; 143(11): 4243 - 4248. [Abstract] [Full Text] [PDF]

				G. Binder, E. Keller, M. Mix, G. G. Massa, W. H. Stokvis-Brantsma, J. M. Wit, and M. B. Ranke Isolated GH Deficiency with Dominant Inheritance: New Mutations, New Insights J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3877 - 3881. [Abstract] [Full Text] [PDF]

				J. Deladoey, P. Stocker, and P. E. Mullis Autosomal Dominant GH Deficiency Due to an Arg183His GH-1 Gene Mutation: Clinical and Molecular Evidence of Impaired Regulated GH Secretion J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3941 - 3947. [Abstract] [Full Text] [PDF]