Growth hormone (GH) deficiency type II: a novel GH-1 gene mutation (GH-R178H) affecting secretion and action.
OBJECTIVE
Main features of the autosomal dominant form of GH deficiency (IGHD II) include markedly reduced secretion of GH combined with low concentrations of IGF-I leading to short stature.


METHODS
A female patient presented with short stature (height -6.0 sd score) and a delayed bone age of 2 yr at the chronological age of 5 yr. Later, at the age of 9 yr, GHD was confirmed by standard GH provocation test, which revealed subnormal concentrations of GH and a very low IGF-I. Genetic analysis of the GH-1 gene revealed the presence of a heterozygous R178H mutation.


RESULTS
AtT-20 cells coexpressing both wt-GH and GH-R178H showed a reduced GH secretion after forskolin stimulation compared with the cells expressing only wt-GH, supporting the diagnosis of IGHD II. Because reduced GH concentrations found in the circulation of our untreated patient could not totally explain her severe short stature, functional characterization of the GH-R178H performed by studies of GH receptor binding and activation of the Janus kinase-2/signal transducer and activator of transcription-5 pathway revealed a reduced binding affinity of GH-R178H for GH receptor and signaling compared with the wt-GH.


CONCLUSIONS
This is the first report of a patient suffering from short stature caused by a GH-1 gene alteration affecting not only GH secretion (IGHD II) but also GH binding and signaling, highlighting the necessity of functional analysis of any GH variant, even in the alleged situation of IGHD II.
Petkovic
Vibor
V
University Children's Hospital, Pediatric Endocrinology, Inselspital CH-3010 Bern, Switzerland.
Godi
Michela
M
Pandey
Amit V
AV
Lochmatter
Didier
D
Buchanan
Charles R
CR
Dattani
Mehul T
MT
Eblé
Andrée
A
Flück
Christa E
CE
Mullis
Primus E
PE
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology; D051379:Mice; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011986:Receptors, Somatotropin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000502:physiology; D015032:Zinc / Q000378:metabolism
D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D019382:Human Growth Hormone; D053614:Janus Kinase 2; D015032:Zinc