Autosomal dominant GH deficiency due to an Arg183His GH-1 gene mutation: clinical and molecular evidence of impaired regulated GH secretion.
J Clin Endocrinol Metab
; 86(8): 3941-7, 2001 Aug.
Article
em En
| MEDLINE
| ID: mdl-11502836
ABSTRACT
G to A transition at position 6664 of the GH-1 gene results in the substitution of Arg183 by His (R183H) in human GH protein and causes a new form of autosomal dominant isolated GH deficiency (type II). Although a weak GH release after standard pharmacological provocation tests is observed in these affected individuals, the dominant inheritance pattern is postulated to be caused by a blockade of the GH-regulated secretion in the somatotrophs. The aim of this study was to analyze the impact of this autosomal dominant mutation not only at a clinical, but also at a cellular, level. The results of the different stimulation tests showed first that the patient possesses a severely impaired, but releasable, GH store, and second that the GH secretion is blocked in a time-dependent and reversible way. To confirm these clinical data, cell culture studies were performed looking at the regulated secretory pathway of GH using AtT-20 cells. Importantly, we were able to show that when the R183H mutant GH was expressed in AtT-20 cells, secretagogue (forskolin) induced a normal R183H GH-regulated secretion, but in AtT-20 cells coexpressing both the R183H mutant GH and the normal GH, forskolin-induced GH secretion was markedly reduced. Together, the experiments seem to support the hypothesis that R183H mutant GH severely impaired the GH-regulated secretion and may, therefore, be the cause of this specific form of isolated GH deficiency type II.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cromossomos Humanos Par 17
/
Hormônio do Crescimento
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Mutação Puntual
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Transtornos do Crescimento
País/Região como assunto:
Asia
/
Europa
Idioma:
En
Revista:
J Clin Endocrinol Metab
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
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