Short stature caused by a mutant growth hormone with an antagonistic effect.
The molecular basis of biologically inactive GH remained unclear until recently. We have very recently reported a child with short stature and a mutant GH caused by a single missense mutation in the GH-1 gene, which itself cannot transduce the GH-signal to the cells but can blunt the action of wild-type GH by virtue of its greater affinity for the GH binding protein (GHBP)/GH receptor. Briefly the clinical features of the patient are: At the age of 4.9 years his height was 81.7 cm (-6.1 SD) and bone age was 2 years. The patient's serum insulin-like growth factor-1 (IGF-1) concentration was 34 ng/ml. The basal serum GH concentration ranged from 7.0 to 14.0 ng/ml and peak concentrations after insulin hypoglycemia, arginine and L-dopa were 38.0, 15.0 and 35.0 ng/ml, respectively. A heterozygous single base substitution was identified in the GH-1 gene of the proband, predicted to convert codon 77 from arginine to cysteine. Isoelectric focusing revealed the presence of an abnormal GH peak in addition to a normal GH peak. The affinity of expressed mutant GH to GHBP was approximately 6 times higher than that of wild-type GH. The mutant GH not only failed to stimulate tyrosine phosphorylation by itself, but it also inhibited the activity of wild-type GH when added simultaneously even in a one tenth dose of wild-type GH. The child whom we reported is therefore the first case of short stature caused by mutant GH with an antagonistic effect.
Takahashi
Y
Y
Department of Medicine, Kobe University School of Medicine, Japan.
Kaji
H
H
Okimura
Y
Y
Goji
K
K
Abe
H
H
Chihara
K
K
D000365:Age Determination by Skeleton; D001827:Body Height; D002352:Carrier Proteins / Q000378:metabolism; D002675:Child, Preschool; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007525:Isoelectric Focusing; D008297:Male; D009154:Mutation; D019000:Phosphotyrosine / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism
D002352:Carrier Proteins; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D019000:Phosphotyrosine; C051815:somatotropin-binding protein