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Department of Pharmacology, Yale University School of Medicine (M.S.L., S.S.K., P.S.D.), New Haven, Connecticut 06520; the Department of Pediatrics, Cornell University Medical College (M.P.W., J.W., R.L.), New York, New York 10021; the Department of Pediatrics, Johns Hopkins University School of Medicine (L.P.P.), Baltimore, Maryland 21287; and the Department of Pediatrics, Columbia University College of Physicians and Surgeons (J.M.G., R.L.), New York, New York 10032
Address all correspondence and requests for reprints to: Priscilla S. Dannies, Yale University School of Medicine, 333 Cedar Street, Department of Pharmacology, New Haven, Connecticut 06520-8066.
Familial isolated GH deficiency type II is an autosomal dominant form of short stature, associated in some families with mutations that result in missplicing to produce del32–71-GH, a protein that cannot fold normally. The mechanism by which this mutant suppresses the secretion of wild-type GH encoded by the normal allele is not known. Coexpression of del32–71-GH with wild-type human GH in transient transfections of the neuroendocrine cell lines GH4C1 and AtT20 suppressed accumulation of wild-type GH. The suppression of wild-type GH accumulation by del32–71-GH was a posttranslational effect on wild-type GH caused by decreased stability, rather than decreased synthesis, of wild-type GH. Coexpression of del32–71-GH with human PRL did not suppress accumulation of PRL, indicating that there was not a general suppression of secretory pathway function. Accumulation of del32–71-GH protein was not necessary for the suppression of wild-type GH, because del32–71-GH did not accumulate in the neuroendocrine cell lines in which suppression of accumulation of wild-type GH was observed. Del32–71-GH did accumulate in transfected COS and CHO cells, but did not suppress the accumulation of wild-type GH in these cells. These studies suggest that del32–71-GH may cause GH deficiency in somatotropes of heterozygotes expressing both wild-type and del32–71-GH by decreasing the intracellular stability of wild-type GH.
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