Biological effect of a novel mutation in the third leucine-rich repeat of human luteinizing hormone receptor.
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.
Leung
Michael Yiu-Kwong
MY
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.
Steinbach
Peter J
PJ
Bear
Deborah
D
Baxendale
Vanessa
V
Fechner
Patricia Y
PY
Rennert
Owen M
OM
Chan
Wai-Yee
WY
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
D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins; D011974:Receptors, LH; D000242:Cyclic AMP