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.
机构:
GENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USAGENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USA
BASS, SH
MULKERRIN, MG
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机构:
GENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USAGENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USA
MULKERRIN, MG
WELLS, JA
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h-index: 0
机构:
GENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USAGENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USA
机构:
GENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USAGENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USA
BASS, SH
MULKERRIN, MG
论文数: 0引用数: 0
h-index: 0
机构:
GENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USAGENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USA
MULKERRIN, MG
WELLS, JA
论文数: 0引用数: 0
h-index: 0
机构:
GENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USAGENENTECH INC, DEPT PROT ENGN, 460 PT SAN BRUNO BLVD, San Francisco, CA 94080 USA