title: A novel inactivating mutation of the LH/chorionic gonadotrophin receptor with impaired membrane trafficking leading to Leydig cell hypoplasia type 1.
abstract: OBJECTIVE
  The LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in the LHCGR gene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familial LHCGR mutation.
  
  
  METHODS
  Five affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed.
  
  
  RESULTS
  The five affected patients were all homozygous for a novel mutation in the LHCGR gene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C-terminal intracellular domain. In vitro studies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small-molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin.
  
  
  CONCLUSIONS
  This novel LHCGR mutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFa
authors: Adolfo
authors: A
authors: Rivero-Müller
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Iulia
authors: I
authors: Potorac
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Axelle
authors: A
authors: Pintiaux
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Adrian F
authors: AF
authors: Daly
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Albert
authors: A
authors: Thiry
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Catherine
authors: C
authors: Rydlewski
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Michelle
authors: M
authors: Nisolle
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Anne-Simone
authors: AS
authors: Parent
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium.
authors: Ilpo
authors: I
authors: Huhtaniemi
authors: Department of PhysiologyInstitute for Biomedicine, University of Turku, Turku, FinlandDepartment of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumFaculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, FinlandDepartment of Biochemistry and Molecular BiologyMedical University of Lublin, 20-093 Lublin, PolandDepartment of Surgery and CancerImperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Campus, London, UKDepartments of GynecologyAnatomopathologyCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Medical GeneticsErasme Hospital, Brussels, BelgiumDepartment of PediatricsCHU de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium albert.beckers@chu.ulg.ac.be.
authors: Albert
authors: A
authors: Beckers
mesh_terms: D000328:Adult; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007247:Infertility, Female / Q000235:genetics; D008297:Male; D021381:Protein Transport / Q000235:genetics*; D011974:Receptors, LH / Q000235:genetics*; D035781:Siblings; D015398:Signal Transduction / Q000235:genetics*; D013737:Testis / Q000002:abnormalities*
chemical_list: D011974:Receptors, LH