LACK OF HORMONE BINDING IN COS-7 CELLS EXPRESSING A MUTATED GROWTH-HORMONE RECEPTOR FOUND IN LARON DWARFISM

被引:26
作者
EDERY, M
ROZAKISADCOCK, M
GOUJON, L
FINIDORI, J
LEVIMEYRUEIS, C
PALY, J
DJIANE, J
POSTELVINAY, MC
KELLY, PA
机构
[1] FAC NECKER ENFANTS MALAD,INSERM,U344,F-75015 PARIS,FRANCE
[2] INRA,UNITE ENDOCRINOL MOLEC,F-78352 JOUY EN JOSAS,FRANCE
[3] MCGILL UNIV,ROYAL VICTORIA HOSP,MOLEC ENDOCRINOL LAB,MONTREAL H3A 1A1,QUEBEC,CANADA
关键词
GENE; POINT MUTATION; MUTAGENESIS; GROWTH HORMONE; PROLACTIN; RECEPTOR; BINDING PROTEIN;
D O I
10.1172/JCI116304
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
A single point mutation in the growth hormone (GH) receptor gene generating a Phe --> Ser substitution in the extracellular binding domain of the receptor has been identified in one family with Laron type dwarfism. The mutation was introduced by site-directed mutagenesis into cDNAs encoding the full-length rabbit GH receptor and the extracellular domain or binding protein (BP) of the human and rabbit GH receptor, and also in cDNAs encoding the full length and the extracellular domain of the related rabbit prolactin (PRL) receptor. All constructs were transiently expressed in COS-7 cells. Both wild type and mutant full-length rabbit GH and PRL receptors, as well as GH and prolactin BPs (wild type and mutant), were detected by Western blot in cell membranes and concentrated culture media, respectively. Immunofluorescence studies showed that wild type and mutant full-length GH receptors had the same cell surface and intracellular distribution and were expressed with comparable intensities. In contrast, all mutant forms (full-length receptors or BPs), completely lost their ability to bind ligand. These results clearly demonstrate that this point mutation (patients with Laron syndrome) does not modify the synthesis or the intracellular pathway of receptor proteins, but rather abolishes ability of the receptor or BP to bind GH and is thus responsible for the extreme GH resistance in these patients.
引用
收藏
页码:838 / 844
页数:7
相关论文
共 28 条
  • [1] RECURRENT NONSENSE MUTATIONS IN THE GROWTH-HORMONE RECEPTOR FROM PATIENTS WITH LARON DWARFISM
    AMSELEM, S
    SOBRIER, ML
    DUQUESNOY, P
    RAPPAPORT, R
    POSTELVINAY, MC
    GOURMELEN, M
    DALLAPICCOLA, B
    GOOSSENS, M
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1991, 87 (03) : 1098 - 1102
  • [2] LARON DWARFISM AND MUTATIONS OF THE GROWTH HORMONE-RECEPTOR GENE
    AMSELEM, S
    DUQUESNOY, P
    ATTREE, O
    NOVELLI, G
    BOUSNINA, S
    POSTELVINAY, MC
    GOOSSENS, M
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1989, 321 (15) : 989 - 995
  • [3] BASS S, 1990, NEW ENGL J MED, V322, P854
  • [4] A SYSTEMATIC MUTATIONAL ANALYSIS OF HORMONE-BINDING DETERMINANTS IN THE HUMAN GROWTH-HORMONE RECEPTOR
    BASS, SH
    MULKERRIN, MG
    WELLS, JA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (10) : 4498 - 4502
  • [5] ABSENCE OF THE PLASMA GROWTH HORMONE-BINDING PROTEIN IN LARON-TYPE DWARFISM
    BAUMANN, G
    SHAW, MA
    WINTER, RJ
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1987, 65 (04) : 814 - 816
  • [6] ABSENCE OF SERUM GROWTH-HORMONE BINDING-PROTEIN IN PATIENTS WITH GROWTH-HORMONE RECEPTOR DEFICIENCY (LARON DWARFISM)
    DAUGHADAY, WH
    TRIVEDI, B
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (13) : 4636 - 4640
  • [7] DEVOS AM, 1992, SCIENCE, V255, P257
  • [8] DEFECTIVE MEMBRANE EXPRESSION OF HUMAN GROWTH-HORMONE (GH) RECEPTOR CAUSES LARON-TYPE GH INSENSITIVITY SYNDROME
    DUQUESNOY, P
    SOBRIER, ML
    AMSELEM, S
    GOOSSENS, M
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (22) : 10272 - 10276
  • [9] IDENTIFICATION AND SEQUENCE-ANALYSIS OF A 2ND FORM OF PROLACTIN RECEPTOR BY MOLECULAR-CLONING OF COMPLEMENTARY-DNA FROM RABBIT MAMMARY-GLAND
    EDERY, M
    JOLICOEUR, C
    LEVIMEYRUEIS, C
    DUSANTERFOURT, I
    PETRIDOU, B
    BOUTIN, JM
    LESUEUR, L
    KELLY, PA
    DJIANE, J
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (06) : 2112 - 2116
  • [10] CHARACTERIZATION OF THE HUMAN GROWTH-HORMONE RECEPTOR GENE AND DEMONSTRATION OF A PARTIAL GENE DELETION IN 2 PATIENTS WITH LARON-TYPE DWARFISM
    GODOWSKI, PJ
    LEUNG, DW
    MEACHAM, LR
    GALGANI, JP
    HELLMISS, R
    KERET, R
    ROTWEIN, PS
    PARKS, JS
    LARON, Z
    WOOD, WI
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (20) : 8083 - 8087