GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function

The growth hormone–releasing hormone receptor (GHRHR) is a member of the family of G protein–coupled receptors that is expressed on pituitary somatotrope cells and mediates the actions of GHRH in stimulating growth hormone (GH) synthesis and secretion. We report that the Ghrhr gene is located in the middle of mouse chromosome 6 in the same region as the little mutation. Mice homozygous for this mutation have reduced GH secretion and a dwarf phenotype. A missense mutation was identified in the extracellular domain of the little GHRHR that disrupts receptor function, suggesting that the growth deficit in these mice results from a defect in the GHRHR. Similar alterations in GHRHR might explain some isolated GH deficiencies in humans.

[1]  T. Deerinck,et al.  The pituitary-specific transcription factor GHF-1 is a homeobox-containing protein , 1988, Cell.

[2]  M. Dufau,et al.  Growth hormone-releasing hormone is produced by rat Leydig cell in culture and acts as a positive regulator of Leydig cell function. , 1992, Endocrinology.

[3]  Y. Kaziro,et al.  Molecular cloning and expression of a cDNA encoding the secretin receptor. , 1991, The EMBO journal.

[4]  K. Catt,et al.  Receptor-mediated actions of growth hormone releasing factor on granulosa cell differentiation. , 1990, Endocrinology.

[5]  Soma Das,et al.  Mutations in the V2 vasopressin receptor gene are associated with X–linked nephrogenic diabetes insipidus , 1992, Nature Genetics.

[6]  L. Staudt,et al.  Chromosomal location of the octamer transcription factors, Otf-1, Otf-2, and Otf-3, defines multiple Otf-3-related sequences dispersed in the mouse genome. , 1991, Genomics.

[7]  L. Donahue,et al.  Growth hormone deficiency in 'little' mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, -1 or -4. , 1993, The Journal of endocrinology.

[8]  M. Rosenfeld,et al.  Pit-1-dependent expression of the receptor for growth hormone releasing factor mediates pituitary cell growth , 1992, Nature.

[9]  Larry W. Swanson,et al.  Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1 , 1990, Nature.

[10]  K. Yoshinaga,et al.  Immunoreactive growth hormone-releasing hormone in rat placenta. , 1988, Endocrinology.

[11]  J. Nadeau,et al.  Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function , 1993, Cell.

[12]  E. Eicher,et al.  Stimulation of growth in the little mouse. , 1976, The Journal of endocrinology.

[13]  N. Vamvakopoulos,et al.  Expression and localization of growth hormone-releasing hormone messenger ribonucleic acid in rat placenta: in vitro secretion and regulation of its peptide product. , 1990, Endocrinology.

[14]  B. Thorens.  Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[15]  E. L. Green.  Linkage, recombination and mapping , 1981 .

[16]  N. Ling,et al.  Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. , 1982, Science.

[17]  K. Mayo.  Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. , 1992, Molecular endocrinology.

[18]  P. Sawchenko,et al.  Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant , 1991, Nature.

[19]  J. Jansson,et al.  Receptor-associated resistance to growth hormone-releasing factor in dwarf "little" mice. , 1986, Science.

[20]  K. Catt,et al.  Expression of the growth hormone-releasing hormone gene and its peptide product in the rat ovary. , 1992, Endocrinology.

[21]  N. B. Johnson,et al.  Interaction of growth hormone-releasing hormone with the insulin-like growth-factors during prenatal development in the rat. , 1991, Endocrinology.

[22]  O. Pescovitz,et al.  Ontogeny and pituitary regulation of testicular growth hormone-releasing hormone-like messenger ribonucleic acid. , 1990, Endocrinology.

[23]  B. Seed,et al.  Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Palkovits,et al.  Electron microscopic immunocytochemical evidence for the existence of bidirectional synaptic connections between growth hormone-releasing hormone- and somatostatin-containing neurons in the hypothalamus of the rat , 1989, Brain Research.

[25]  A. Bartke,et al.  Etiology of growth hormone deficiency in little, Ames, and Snell dwarf mice. , 1983, Endocrinology.

[26]  G. Watanabe,et al.  Dynamics of ovarian inhibin secretion during the oestrous cycle of the rat. , 1990, The Journal of endocrinology.

[27]  R. Hammer,et al.  Dramatic pituitary hyperplasia in transgenic mice expressing a human growth hormone-releasing factor gene. , 1988, Molecular endocrinology.

[28]  M. Rosenfeld,et al.  A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype , 1988, Cell.

[29]  K. Kovacs,et al.  Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor. , 1982, The Journal of clinical investigation.

[30]  S. Asa,et al.  Pituitary adenomas in mice transgenic for growth hormone-releasing hormone. , 1992, Endocrinology.

[31]  W. Beamer,et al.  Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. , 1976, The Journal of heredity.

[32]  S. Suhr,et al.  Mouse growth-hormone-releasing hormone: precursor structure and expression in brain and placenta. , 1989, Molecular endocrinology.

[33]  N. Copeland,et al.  Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus , 1982, Journal of virology.

[34]  M. Karin,et al.  Regulation of the pituitary-specific homeobox gene GHF1 by cell-autonomous and environmental cues , 1990, Nature.

[35]  M. Greenberg,et al.  CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. , 1991, Science.

[36]  F J Grant,et al.  Expression cloning and signaling properties of the rat glucagon receptor. , 1993, Science.

[37]  R. Palmiter,et al.  Partial correction of murine hereditary growth disorder by germ-line incorporation of a new gene , 1984, Nature.

[38]  N. Copeland,et al.  Development and applications of a molecular genetic linkage map of the mouse genome. , 1991, Trends in genetics : TIG.

[39]  M. Freeman,et al.  A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. , 1991, Science.

[40]  G. Snell.  DWARF, A NEW MENDELIAN RECESSIVE CHARACTER OF THE HOUSE MOUSE. , 1929, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Bichet,et al.  Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus , 1992, Nature.

[42]  T. L. McGee,et al.  Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[43]  H. Lodish,et al.  Expression cloning of an adenylate cyclase-coupled calcitonin receptor. , 1991, Science.

[44]  M. Montminy,et al.  Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133 , 1989, Cell.

[45]  E. L. Green.  Genetics and probability in animal breeding experiments. , 1981 .

[46]  T. L. McGee,et al.  A Null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa , 1992, Nature Genetics.

[47]  T. Sano,et al.  Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations. , 1988, Endocrine reviews.

[48]  R. Shigemoto,et al.  Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide , 1992, Neuron.

[49]  J. Darnell,et al.  Production of mRNA in chinese hamster cells: Relationship of the rate of synthesis to the cytoplasmic concentration of nine specific mRNA sequences , 1979, Cell.

[50]  K. Mayo,et al.  Cellular localization and hormonal regulation of follicle-stimulating hormone and luteinizing hormone receptor messenger RNAs in the rat ovary. , 1991, Molecular endocrinology.

[51]  G. Hoffman,et al.  Isolated deficiency of immunocytochemically detected somatostatin in Snell dwarf, but not in “little,” mice , 1987, Peptides.

[52]  M. Thorner,et al.  Molecular cloning and expression of a human anterior pituitary receptor for growth hormone-releasing hormone. , 1993, Molecular endocrinology.

[53]  W. Vale,et al.  Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour , 1982, Nature.

[54]  K. M. Gianola,et al.  A highly conserved mouse gene with a propensity to form pseudogenes in mammals , 1988, Molecular and cellular biology.