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Prolonged Retention after Aggregation into Secretory Granules of Human R183H-Growth Hormone (GH), a Mutant that Causes Autosomal Dominant GH Deficiency Type II

Department of Pharmacology (Y.L.Z., P.S.D.), Yale University School of Medicine, New Haven, Connecticut 06520; and Physiology and Pharmacology Department and Institute for Molecular Bioscience (B.C.-C., M.J.W.), University of Queensland, St. Lucia 4072, Australia

Address all correspondence and requests for reprints to: Priscilla S. Dannies, Yale University School of Medicine, Department of Pharmacology, 333 Cedar Street, New Haven, Connecticut 06520-8066. E-mail: priscilla.dannies{at}yale.edu.

Human R183H-GH causes autosomal dominant GH deficiency type II. Because we show here that the mutant hormone is fully bioactive, we have sought to locate an impairment in its progress through the secretory pathway as assessed by pulse chase experiments. Newly synthesized wild-type and R183H-GH were stable when expressed transiently in AtT20 cells, and both formed equivalent amounts of Lubrol-insoluble aggregates within 40 min after synthesis. There was no evidence for intermolecular disulfide bond formation in aggregates of wild-type hormone or the R183H mutant. Both wild-type and R183H-GH were packaged into secretory granules, assessed by the ability of 1 mM BaCl₂ to stimulate release and by immunocytochemistry. The mutant differed from wild-type hormone in its retention in the cells after packaging into secretory granules; 50% more R183H-GH than wild-type aggregates were retained in AtT20 cells 120 min after synthesis, and stimulated release of R183H-GH or a mixture of R183H-GH and wild-type that had been retained in the cell was reduced. The longer retention of R183H-GH aggregates indicates that a single point mutation in a protein contained in secretory granules affects the rate of secretory granule release.

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