Mechanism of female CHH caused by compound heterozygous mutations in the LHB gene

Hailu Ma; Chenyang Li; Jingxi Gao; Wenjing Wu; Zhao Sun; Xi Wang; Min Nie; Xueyan Wu; Jiangfeng Mao; Qin Han

doi:10.1007/s10815-024-03307-2

Mechanism of female CHH caused by compound heterozygous mutations in the LHB gene

J Assist Reprod Genet. 2025 Jan 9. doi: 10.1007/s10815-024-03307-2. Online ahead of print.

Authors

Hailu Ma^#¹, Chenyang Li^#¹, Jingxi Gao², Wenjing Wu², Zhao Sun³, Xi Wang¹, Min Nie¹, Xueyan Wu¹, Jiangfeng Mao⁴, Qin Han⁵

Affiliations

¹ Department of Endocrinology, Dongcheng District, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, PekingBeijing, 100730, China.
² Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, School of Basic Medicine, Center of Excellence in Tissue Engineering of Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital, Beijing Key Laboratory, PekingBeijing, 100730, China.
³ Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, PekingBeijing, 100730, China.
⁴ Department of Endocrinology, Dongcheng District, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, PekingBeijing, 100730, China. maojf@pumch.cn.
⁵ Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, School of Basic Medicine, Center of Excellence in Tissue Engineering of Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College Hospital, Beijing Key Laboratory, PekingBeijing, 100730, China. hanqin@ibms.pumc.edu.cn.

^# Contributed equally.

PMID: 39786527
DOI: 10.1007/s10815-024-03307-2

Abstract

Background: Luteinizing hormone (LH) plays a crucial role in the postnatal development and maturation of gonads. Inactivating mutations of the luteinizing hormone beta subunit (LHB)gene are extremely rare and can result in congenital hypogonadotropic hypogonadism (CHH).

Methods: We conducted DNA sequencing on an 18-year-old female patient with undetectable LH and clinical symptoms of CHH. Pulsatile GnRH was administered to promote puberty development. In vitro construction of mutant genes, confocal microscopy, and protein functional assays were used to investigate the effects of genetic variants on hormone function and secretion. Experiments were conducted in HEK293T cells to examine the colocalization and dimerization of LH subunits, as well as to measure intracellular and extracellular LH concentrations.

Results: Compound heterozygous mutations of c.252C>G (p.F84L) and c.364G>A (p.G122S) were found in the patient's genome. Pulsatile GnRH therapy was effective in promoting puberty development and ovulation. The LH alpha subunit was found to co-localize with both mutant beta subunits after immunofluorescence staining, and immunoprecipitation detected the dimerization of the LH alpha subunit with both mutant beta subunits. Higher intracellular LH concentrations and lower extracellular LH concentrations compared to the wild type indicate secretion dysfunction for LH.

Conclusion: Compound heterozygous mutations of c.252C>G (p.F84L) and c.364G>A (p.G122S) in the LHB gene may lead to CHH for female patient. These mutations do not impair the expression and dimerization of the alpha and beta subunits, but they do prevent the secretion of LH. The study expands our understanding of the clinical manifestation of LHB gene mutations in females and provides a treatment for these patients.

Keywords: Female infertility; Hypogonadotropic hypogonadism; Luteinizing hormone; Luteinizing hormone beta subunit; Selective luteinizing hormone deficiency.