NOVEL COMPOUND HETEROZYGOUS MUTATIONS OF GROWTH-HORMONE (GH) RECEPTORGENE IN A PATIENT WITH GH INSENSITIVITY SYNDROME

A girl with severe growth retardation had the clinical features of Lar on syndrome. Her serum insulin-like growth factor-I level was complete ly unresponsive to exogenous GH administration. The serum GH-binding p rotein (GHBP) level was below the detectable limit in the patient, but it was normal in her parents and brother. Her parents and brother wer e normal in their height. Amplification with PCR and direct sequencing of her GH receptor gene revealed compound heterozygous mutations. The allele hom her mother contained a transversion of G to T in exon 7 th at could introduce a stop codon in place of a glutamic acid at amino a cid 224. Another mutation was found in the allele in her father and al so identified in her brother. It was a C deletion at position 981 in e xon 10 that could introduce a frame shift, thereby causing the product ion of 20 novel amino acids (310-329) instead of the wild-type sequenc e, the premature termination at codon 330, and the subsequent deletion of the C terminal portion of the intracellular domain. RT-PCR of her father's lymphocytes and sequencing of its complementary DNA revealed that only the wildtype GH receptor messenger RNA was expressed in his lymphocytes, though the mechanism remains unclear. These results sugge st that neither of the mutant alleles could generate a functional GH r eceptor, which would be consistent with the patient's severe growth re tardation and undetectable serum GHBP.