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.

How to Train a Cell–Cutting-Edge Molecular Tools

“…While the WT LHB-mCherry was normally secreted, and only visible inside secretion vesicles, the mutant was intracellularly retained. Nuclear-AmCyan was then used to quantify for equal expression (Potorac et al, 2016). …”

Morphometric Evaluation of Spermatogenic Cells and Seminiferous Tubules and Exploration of Luteinizing Hormone Beta Polypeptide in Testis of Datong Yak

“…LHB plays an essential role in the mammalian fertilization process [18]. Another study speculated that LH helps in ovulation, spermatogenesis, and the stimulation of ovaries and testis to synthesize steroid hormones [7]. However, all these findings were observed in other species, but no information has been published related to histomorphological changes and expression profiling of LHB in testis of yak at different ages.…”

“…Luteinizing hormone βeta polypeptide (LHB) is a member of the beta chain family of glycoprotein hormones [7]. These glycoproteins are complex hormonally active macromolecules [8].…”

Comment on “Hypogonadotrophic hypogonadism due to a mutation in the luteinizing hormone β-subunit gene”

“…Our three male patients with documented LHB mutations that were treated with human chorionic gonadotropin (hCG) (Pregnyl, MSD, Brussels, Belgium) 5,000 IU/week for nearly 2 years had virilization and testicular growth, and spermatogenesis can occur, although it is usually suboptimal [3-5]. Our initial male patient successfully underwent assisted reproduction [4], and had recently a second child via the same method.…”