Autosomal dominant growth hormone (GH) deficiency type II: The Del32-71-GHdeletion mutant suppresses secretion of wild-type GH

Familial isolated GH deficiency type II is an autosomal dominant form of sh ort stature, associated in some families with mutations that result in miss plicing to produce del32-71-GH, a protein that cannot fold normally. The me chanism by which this mutant suppresses the secretion of wild-type GH encod ed 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 GH(4)C(1) and AtT20 suppressed accumulation of wild-type GH. The suppressio n of wild-type GH accumulation by del32-71-GH was a posttranslational effec t on wild-type GH caused by decreased stability, rather than decreased synt hesis, 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 suppr ession of secretory pathway function. Accumulation of del32-71-GH protein w as not necessary for the suppression of wild-type GH, because del32-71-GH d id not accumulate in the neuroendocrine cell lines in which suppression of accumulation of wildtype GH was observed. Del32-71-GH did accumulate in tra nsfected COS and CHO cells, but did not suppress the accumulation of wildty pe GH in these cells. These studies suggest that del32-71-GH may cause GH d eficiency in somatotropes of heterozygotes expressing both wild-type and de l32-71-GH by decreasing the intracellular stability of wild-type GH.