A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation.

Details

Serval ID
serval:BIB_B846ED1016E1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation.
Journal
The Journal of endocrinology
Author(s)
Potorac I., Rivero-Müller A., Trehan A., Kiełbus M., Jozwiak K., Pralong F., Hafidi A., Thiry A., Ménagé J.J., Huhtaniemi I., Beckers A., Daly A.F.
ISSN
1479-6805 (Electronic)
ISSN-L
0022-0795
Publication state
Published
Issued date
12/2016
Peer-reviewed
Oui
Volume
231
Number
3
Pages
197-207
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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.

Pubmed
Open Access
Yes
Create date
29/09/2016 18:41
Last modification date
20/08/2019 15:26
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