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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.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

Inhibition of Growth Hormone (GH) Secretion by a Mutant<i>GH-I</i>Gene Product in Neuroendocrine Cells Containing Secretory Granules: An Implication for Isolated GH Deficiency Inherited in an Autosomal Dominant Manner<sup>1</sup>

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

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