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Background <p>Luteinizing hormone (LH) plays a crucial role in the postnatal development and maturation of gonads. Inactivating mutations of the luteinizing hormone beta subunit (<i>LHB</i>)gene are extremely rare and can result in congenital hypogonadotropic hypogonadism (CHH).</p> Methods <p>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.</p> Results <p>Compound heterozygous mutations of c.252C&gt;G (p.F84L) and c.364G&gt;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.</p> Conclusion <p>Compound heterozygous mutations of c.252C&gt;G (p.F84L) and c.364G&gt;A (p.G122S) in the <i>LHB</i>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 <i>LHB</i>gene mutations in females and provides a treatment for these patients.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月9日

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

摘要

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 LHBgene 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 LHBgene mutations in females and provides a treatment for these patients.