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 encod...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2000-03, Vol.141 (3), p.883-890
Main Authors: Lee, M S, Wajnrajch, M P, Kim, S S, Plotnick, L P, Wang, J, Gertner, J M, Leibel, R L, Dannies, P S
Format: Article
Language:English
Subjects:
Cell Line
Cells, Cultured
DNA, Complementary
Electrophoresis, Polyacrylamide Gel
Gene Deletion
Genetic Vectors
Human Growth Hormone - deficiency
Human Growth Hormone - genetics
Human Growth Hormone - metabolism
Humans
Mutation - physiology
Pituitary Gland - cytology
Pituitary Gland - metabolism
Protein Folding
RNA, Messenger - biosynthesis
Sulfhydryl Compounds - metabolism
Transfection
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Summary: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.
ISSN:0013-7227
DOI:10.1210/en.141.3.883