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Biological Effect of a Novel Mutation in the Third Leucine-Rich Repeat of Human Luteinizing Hormone Receptor

Laboratory of Clinical Genomics (M.Y.-K.L., D.B., V.B., O.M.R., W.-Y.C.), National Institute of Child Health and Human Development, and Center for Molecular Modeling (P.J.S.), Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892; Department of Pediatrics (P.Y.F.), Stanford University, Stanford, California 94305; and Department of Pediatrics (W.-Y.C.), Georgetown University, Washington, D.C. 20007

Address all correspondence and requests for reprints to: Dr. Wai-Yee Chan, Laboratory of Clinical Genomics, National Institute of Child Health and Human Development, National Institutes of Health, Building 49, Room 2A08, 49 Convent Drive, MSC 4429, Bethesda, Maryland 20892-4429. E-mail: chanwy{at}mail.nih.gov.

A novel heterozygous mutation A340T leading to the substitution of Phe for the conserved amino acid Ile114 was identified by nucleotide sequencing of the human LH/chorionic gonadotropin receptor (hLHR) of a patient with Leydig cell hypoplasia. This mutation is located in the third leucine-rich repeat in the ectodomain of the hLHR. In vitro expression studies demonstrated that this mutation results in reduced ligand binding and signal transduction of the receptor. Studies of hLHR constructs in which various amino acids were substituted for the conserved Ile114 showed that receptor activity is sensitive to changes in size, shape, and charge of the side chain. A homology model of the wild-type hLHR ectodomain was made, illustrating the packing of conserved hydrophobic side chains in the protein core. Substitution of Ile114 by Phe might disrupt intermolecular contacts between hormone and receptor. This mutation might also affect an LHR-dimer interaction. Thus, the I114F mutation reduces ligand binding and signal transduction by the hLHR, and it is partially responsible for Leydig cell hypoplasia in the patient.