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 μg/liter during hypoglycemia, IGF-I 8.0 μg/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 μg/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 w...