title: A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation.
abstract: Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.
authors.affiliation: Department of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium.
authors.forename: Iulia
authors.initials: I
authors.lastname: Potorac
authors.affiliation: Department of PhysiologyInstitute of Biomedicine, University of Turku, Turku, Finland.|Faculty of Natural Sciences and TechnologyÅbo Akademi University, Turku, Finland.|Department of Biochemistry and Molecular BiologyMedical University of Lublin, Lublin, Poland.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Rivero-Müller
authors.affiliation: Department of PhysiologyInstitute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Trehan
authors.affiliation: Department of Biochemistry and Molecular BiologyMedical University of Lublin, Lublin, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Kiełbus
authors.affiliation: Laboratory of Medicinal Chemistry and NeuroengineeringMedical University of Lublin, Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Service of EndocrinologyDiabetology and Metabolism, Department of Medicine, CHU Vaudois, Lausanne, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Pralong
authors.affiliation: Department of Diabetology and Metabolic DiseasesCentre Hospitalier Universitaire Ibn Sina, Rabat, Morocco.
authors.forename: Aicha
authors.initials: A
authors.lastname: Hafidi
authors.affiliation: Department of PathologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium.
authors.forename: Albert
authors.initials: A
authors.lastname: Thiry
authors.affiliation: Endocrinology PracticeFontainebleau, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Ménagé
authors.affiliation: Department of PhysiologyInstitute of Biomedicine, University of Turku, Turku, Finland.|Department of Surgery and CancerInstitute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, London, UK.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.affiliation: Department of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium albert.beckers@chu.ulg.ac.be.
authors.forename: Albert
authors.initials: A
authors.lastname: Beckers
authors.affiliation: Department of EndocrinologyCentre Hospitalier Universitaire de Liège, Université de Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Daly
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001693:Biological Transport, Active; D006063:Chorionic Gonadotropin / Q000627:therapeutic use; D003241:Consanguinity; D005058:Eunuchism / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D037101:Luteinizing Hormone, beta Subunit / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D006063:Chorionic Gonadotropin; D037101:Luteinizing Hormone, beta Subunit; D050505:Mutant Proteins; D011994:Recombinant Proteins
keywords: glycoprotein hormone; hypogonadism; luteinizing hormone; mutation