Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT 5 signal transduction.
Congenital GH insensitivity syndrome (GHIS) is usually the result of a mutation in the extracellular domain of the GH receptor (GHR). We report one of only a small number of mutations so far identified within the intracellular domain of the GHR. The probands are a 53-yr-old woman, height 114 cm (SD score, -8.7), peak GH 45 microg/liter during hypoglycemia, IGF-I 8.0 microg/liter [normal range (N) N 54-389], IGF binding protein-3 16 nmol/liter (N 61-254), GHBP 6.8% (N > 10); and her 57-yr-old brother, height 140 cm (SD score, -6), IGF-I 38.8 micro g/liter (N 54-290), IGF binding protein-3 30 nmol/liter (N 61-196). Both patients were homozygous for a 22-bp deletion in the DNA encoding the cytoplasmic domain of the GHR, resulting in a frameshift and premature stop codon. The resultant GHR is truncated at amino acid 449 (GHR1-449) after Box1, the Janus kinase 2 binding domain of the receptor. Functional studies in HEK293 and Chinese hamster ovary cells show GHR1-449 to have a cellular distribution similar to that of the wild-type GHR, judged by binding of iodinated GH, FACS analysis, and immunocytochemistry. Western blot analysis showed GH-induced phosphorylation of Janus kinase 2, signal transducer and activator of transcription (Stat)3, and Erk2 for both GHR1-449 and wild-type GHR. However, no Stat5 activity was detected in cells expressing GHR1-449, consistent with the fact that GHR1-449 contains no Stat5 binding site. In conclusion, we report two adult siblings with GHIS due to a mutation in the intracellular domain of GHR resulting in a selective loss of Stat5 signaling. Results are consistent with the hypothesis that the loss of signaling through the Stat5 pathway results in GHIS.
Milward
A
A
Division of Clinical Sciences (North), University of Sheffield, Sheffield S5 7AU, United Kingdom.
Metherell
L
L
Maamra
M
M
Barahona
M J
MJ
Wilkinson
I R
IR
Camacho-Hübner
C
C
Savage
M O
MO
Bidlingmaier
M
M
Bidlingmaier
C M
CM
Clark
A J L
AJ
Ross
R J M
RJ
Webb
S M
SM
D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008894:Milk Proteins; D008969:Molecular Sequence Data; D010641:Phenotype; D011388:Prolactin / Q000378:metabolism; D011485:Protein Binding; D011986:Receptors, Somatotropin / Q000235:genetics* / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011986:Receptors, Somatotropin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019382:Human Growth Hormone; D011388:Prolactin