title: A novel missense homozygous inactivating mutation in the fourth transmembrane helix of the luteinizing hormone receptor in leydig cell hypoplasia.
abstract: Loss-of-function mutations/inactivating mutations of the human chorionic gonadotropin/luteinizing hormone receptor (hCG/LHR), a G-protein coupled receptor, lead to impaired Leydig cell differentiation. Leydig cell hypoplasia/agenesis/dysplasia (LCH) is one of the causes of male pseudohermaphroditism (MPH). We studied a 19-year-old MPH patient with female phenotype and 46,XY karyotype. Testicular histology and hormonal profile of the patient is typical of LCH. Nucleotide sequencing of exon 11 of hLHR identified a novel T1505C transversion mutation. The mutation is homozygous in the patient and is heterozygous in both parents. The single base mutation caused the substitution of a conserved leucine at 502 position to proline in transmembrane helix (TM) IV of the hLHR. This is the first LCH causing mutation identified in TM IV of the hLHR. Expression study of the mutated hLHR in human embryonic kidney (HEK)293 cells showed reduced cAMP production and ligand binding. Receptor trafficking was not affected by the mutation when the green fluorescence protein conjugated mutated receptor was expressed in HEK293 cells. The mutation caused inactivation of the hLHR and resulted in LCH in the patient.
authors.affiliation: Section on Developmental Genomics, Laboratory of Clinical Genomics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 50892-4429, USA.
authors.forename: Michael Yiu-Kwong
authors.initials: MY
authors.lastname: Leung
authors.forename: Osama
authors.initials: O
authors.lastname: Al-Muslim
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Wu
authors.forename: Andrew
authors.initials: A
authors.lastname: Aziz
authors.forename: Sohail
authors.initials: S
authors.lastname: Inam
authors.forename: Mohammed
authors.initials: M
authors.lastname: Awadh
authors.forename: Owen M
authors.initials: OM
authors.lastname: Rennert
authors.forename: Wai-Yee
authors.initials: WY
authors.lastname: Chan
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005836:Genitalia, Female / Q000002:abnormalities; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007621:Karyotyping; D007985:Leydig Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D011869:Radioligand Assay; D011974:Receptors, LH / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000002:abnormalities
chemical_list: D008565:Membrane Proteins; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D004247:DNA