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 hormon e (GH) and IGF-I, proportional reduction in weight and size, and delay in sexual maturation, has much in common with the phenotype of the ho mozygous 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 recepto r 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 G HRH were studied. Restriction endonuclease analysis, linkage studies, and polymerase chain reaction amplification and sequencing of the whol e extracellular domain including the first three membrane spanning dom ains of the GHRH receptor gene were performed. None of the analyses re vealed any structural abnormalities in these patients with IGHD. This suggests that a lit/lit mouse equivalent is an unlikely explanation fo r the majority of children with IGHD. Although gross structural abnorm alities in the whole gene have been ruled out in this study, mutations in the carboxyl terminus are still possible, and, therefore, the rema ining part of the gene needs to be sequenced.