title: Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Lee
authors.forename: M P
authors.initials: MP
authors.lastname: Wajnrajch
authors.forename: S S
authors.initials: SS
authors.lastname: Kim
authors.forename: L P
authors.initials: LP
authors.lastname: Plotnick
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J M
authors.initials: JM
authors.lastname: Gertner
authors.forename: R L
authors.initials: RL
authors.lastname: Leibel
authors.forename: P S
authors.initials: PS
authors.lastname: Dannies
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D018076:DNA, Complementary; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D005822:Genetic Vectors; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000502:physiology*; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D017510:Protein Folding; D012333:RNA, Messenger / Q000096:biosynthesis; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D019382:Human Growth Hormone