Isolated growth hormone deficiency: testing the little mouse hypothesis in man and exclusion of mutations within the extracellular domain of the growth hormone-releasing hormone receptor.

The phenotypic characteristics of isolated growth hormone deficiency (IGHD) type IB in humans, such as autosomal recessive inheritance, time of onset of growth retardation, diminished secretion of growth hormone (GH) and IGF-I, proportional reduction in weight and size, and delay in sexual maturation, has much in common with the phenotype of the homozygous little/little (lit/lit) mouse. Sequencing of the GH releasing hormone (GHRH) receptor in lit/lit mice has shown a single nucleotide substitution within the extracellular peptide binding domain at codon 60 that changed aspartic acid to glycine. Therefore, the GHRH receptor is a reasonable candidate gene for causing IGHD in humans. DNA from 65 unrelated healthy Caucasians of normal stature and 65 children with IGHD type IB of whom 12 did not respond to exogenous treatment with GHRH were studied. Restriction endonuclease analysis, linkage studies, and polymerase chain reaction amplification and sequencing of the whole extracellular domain including the first three membrane spanning domains of the GHRH receptor gene were performed. None of the analyses revealed any structural abnormalities in these patients with IGHD. This suggests that a lit/lit mouse equivalent is an unlikely explanation for the majority of children with IGHD. Although gross structural abnormalities in the whole gene have been ruled out in this study, mutations in the carboxyl terminus are still possible, and, therefore, the remaining part of the gene needs to be sequenced.