Rivero-Müller Adolfo, Potorac Iulia, Pintiaux Axelle, Daly Adrian F, Thiry Albert, Rydlewski Catherine, Nisolle Michelle, Parent Anne-Simone, Huhtaniemi Ilpo, Beckers Albert
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
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.
Eur J Endocrinol. 2015 Jun;172(6):K27-36. doi: 10.1530/EJE-14-1095. Epub 2015 Mar 20.
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.
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.
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.
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.
促黄体生成素/绒毛膜促性腺激素受体（LHCGR）是一种G蛋白偶联受体（GPCR），在男性性分化、卵巢卵泡成熟调节、排卵、黄体维持和妊娠维持以及睾丸睾酮产生维持中起核心作用。LHCGR基因的突变非常罕见。这项工作的目的是研究一种罕见的家族性LHCGR突变的临床和分子特征。
对一个家族的五名受影响成员进行了基因研究，其中包括一名表型为女性但基因型为男性（46,XY）的1型莱迪希细胞发育不全患者以及四名基因型为女性但有生殖异常的兄弟姐妹。进行了细胞转运研究以及突变受体的信号传导研究。
这五名受影响的患者在LHCGR基因中均为一种新突变的纯合子，即第1850位的鸟嘌呤缺失（1850delG）。这导致了移码突变，影响了大部分C末端细胞内结构域。体外研究表明，1850delG受体完全无法转运到细胞膜，被困在内质网中。小分子激动剂治疗无法挽救这种情况，也无法通过共表达结合的人绒毛膜促性腺激素在细胞内进行刺激。
这种新的LHCGR突变由于转运和信号异常导致LHCGR受体完全失活，这增进了我们对受影响的结构域对受体转运和功能影响的理解。
