Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH.
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.
Lee
M S
MS
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Wajnrajch
M P
MP
Kim
S S
SS
Plotnick
L P
LP
Wang
J
J
Gertner
J M
JM
Leibel
R L
RL
Dannies
P S
PS
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
D018076:DNA, Complementary; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D019382:Human Growth Hormone