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Four Contiguous Amino Acid Substitutions, Identified in Patients with Laron Syndrome, Differently Affect the Binding Affinity and Intracellular Trafficking of the Growth Hormone Receptor¹

INSERM U-344, Endocrinologie Moléculaire, Faculté Necker-Enfants Malades (J.W., N.E., M.-C.P.-V., J.F.), 75015 Paris, France; Howard Hughes Medical Institute and Department of Genetics, Stanford University Medical Center (M.A.B., U.F.), Stanford, California 94305; the Department of Pediatrics, University of California Children’s Hospital (M.E.G.), Los Angeles, California 90095-1752; the Department of Pediatrics, King Faisal Specialist Hospital (N.S.), Riyadh 11211, Saudi Arabia; the Department of Pediatrics, Baystate Medical Center Childrens Hospital (E.O.R.), Springfield, Massachusetts 01199; and the Division of Molecular and Genetic Medicine, The Medical School, University of Sheffield, Royal Hallamshire Hospital (S.D.), Sheffield, United Kingdom S10 2JF

Address all correspondence and requests for reprints to: Dr. Joëlle Finidori, INSERM U-344, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France. E-mail: finidori{at}necker.fr

We have analyzed the GH receptor (GHR) gene in four individuals with Laron syndrome, and a missense mutation was identified for each patient in the extracellular domain of the GHR (D152H, I153T, Q154P, and V155G). The D152H mutation was previously reported. We have reproduced the three novel mutations in the GHR complementary DNA and analyzed their consequences in human 293 transfected cells. In cells expressing the I153T and V155G mutants, binding of [¹²⁵I]human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. Binding assays with cells expressing the Q154P mutant revealed severe defects both at the cell surface and in total particulate membrane fractions. Immunofluorescence experiments confirmed that cell surface expression of the three mutants was altered, and colocalization studies suggested that most of the mutant receptors are retained in the endoplasmic reticulum. Endoglycosidase H resistance tests also indicated that the majority of I153T and V155G GHRs are trapped in the endoplasmic reticulum. Thus, mutations on contiguous amino acids of the GHR result in various defects. The I153T, Q154P, and V155G mutations mainly affect intracellular trafficking and binding affinity of the receptor, whereas the D152H mutation affects receptor expression, dimerization, and signaling.

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