Pituitary growth hormone release is under dual hypothalamic control, stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. Childhood growth hormone deficiency (GHD), leading to dwarfism and metabolic dysfunction, can result from a failure of hypothalamic GHRH production or release, from maldevelopment of the pituitary somatotrophes, and from genetic disorders of growth hormone synthesis. Some familial cases of isolated GHD have been attributed to mutations in the growth hormone gene itself but in other families GHD is not linked to this locus. The mouse dwarfism trait, little, is due to a recessively inherited missense mutation (lit) in the extracellular domain of the GHRH receptor (Ghrhr): Pituitary glands of the little mouse are deficient in growth hormone and are unresponsive to GHRH in vivo and in vitro. Somatic growth is increased by systemic administration of human growth hormones. Human GHRHR shows strong sequence homology to the murine gene. The cDNA contains an open reading frame of 1,269 base pairs (bp) coding for a 423-amino acid protein. Having mapped the human homologue (GHRHR) to chromosome 7p15 (ref. 9), we undertook to look for mutations in GHRHR in familial GHD. We now report a nonsense mutation in the human GHRHR gene that results in profound GH deficiency in at least two members of a consanguineous family. Mutations of GHRHR may account for other instances of GH deficiency in which the growth hormone gene is normal.
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