title: Biological effect of a novel mutation in the third leucine-rich repeat of human luteinizing hormone receptor.
abstract: 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.
authors.affiliation: 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, USA.
authors.forename: Michael Yiu-Kwong
authors.initials: MY
authors.lastname: Leung
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Steinbach
authors.forename: Deborah
authors.initials: D
authors.lastname: Bear
authors.forename: Vanessa
authors.initials: V
authors.lastname: Baxendale
authors.forename: Patricia Y
authors.initials: PY
authors.lastname: Fechner
authors.forename: Owen M
authors.initials: OM
authors.lastname: Rennert
authors.forename: Wai-Yee
authors.initials: WY
authors.lastname: Chan
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D007984:Leydig Cell Tumor / Q000235:genetics*; D008297:Male; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D011974:Receptors, LH / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins; D011974:Receptors, LH; D000242:Cyclic AMP