title: Autosomal dominant GH deficiency due to an Arg183His GH-1 gene mutation: clinical and molecular evidence of impaired regulated GH secretion.
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.
authors.affiliation: Division of Pediatric Endocrinology, University Children's Hospital, CH-3010 Bern, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Deladoëy
authors.forename: P
authors.initials: P
authors.lastname: Stocker
authors.forename: P E
authors.initials: PE
authors.lastname: Mullis
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D016466:CHO Cells; D002460:Cell Line; D002648:Child; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D005260:Female; D005799:Genes, Dominant; D006130:Growth Disorders / Q000097:blood / Q000235:genetics*; D013006:Growth Hormone / Q000097:blood / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006639:Histidine; D006801:Humans; D007018:Hypopituitarism / Q000097:blood / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D010375:Pedigree; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis; D013557:Switzerland; D013739:Testosterone / Q000097:blood; D013963:Thyroid Hormones / Q000097:blood; D014162:Transfection; D014421:Turkey / Q000208:ethnology; D044465:White People
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D013963:Thyroid Hormones; D005576:Colforsin; D013739:Testosterone; D006639:Histidine; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D001120:Arginine