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Novel Compound Heterozygous Mutations of Growth Hormone (GH) Receptor Gene in a Patient with GH Insensitivity Syndrome¹

Third Division, Department of Medicine, Kobe University School of Medicine (H.K., Y.T., K.I., T.T., Y.O., H.A., K.C.), Kobe, Japan; Nose Clinic (O.N.), Kobe, Japan; and Department of Pediatrics, Osaka University School of Medicine (H.T.), Osaka, Japan

Address all correspondence and requests for reprints to: Hidesuke Kaji, Third Division, Department of Medicine, Kobe University School of Medicine, Kobe, Japan.

A girl with severe growth retardation had the clinical features of Laron syndrome. Her serum insulin-like growth factor-I level was completely unresponsive to exogenous GH administration. The serum GH-binding protein (GHBP) level was below the detectable limit in the patient, but it was normal in her parents and brother. Her parents and brother were normal in their height. Amplification with PCR and direct sequencing of her GH receptor gene revealed compound heterozygous mutations. The allele from her mother contained a transversion of G to T in exon 7 that could introduce a stop codon in place of a glutamic acid at amino acid 224. Another mutation was found in the allele in her father and also identified in her brother. It was a C deletion at position 981 in exon 10 that could introduce a frame shift, thereby causing the production of 20 novel amino acids (310–329) instead of the wild-type sequence, 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 wild-type GH receptor messenger RNA was expressed in his lymphocytes, though the mechanism remains unclear. These results suggest that neither of the mutant alleles could generate a functional GH receptor, which would be consistent with the patient’s severe growth retardation and undetectable serum GHBP.

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