Ma Hailu, Li Chenyang, Gao Jingxi, Wu Wenjing, Sun Zhao, Wang Xi, Nie Min, Wu Xueyan, Mao Jiangfeng, Han Qin
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.
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.
J Assist Reprod Genet. 2025 Jan;42(1):293-302. doi: 10.1007/s10815-024-03307-2. Epub 2025 Jan 9.
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).
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.
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.
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.
促黄体生成素（LH）在性腺的出生后发育和成熟过程中起着至关重要的作用。促黄体生成素β亚基（LHB）基因的失活突变极为罕见，可导致先天性低促性腺激素性性腺功能减退（CHH）。
我们对一名18岁、促黄体生成素检测不到且有CHH临床症状的女性患者进行了DNA测序。给予脉冲式促性腺激素释放激素（GnRH）以促进青春期发育。通过体外构建突变基因、共聚焦显微镜和蛋白质功能测定来研究基因变异对激素功能和分泌的影响。在人胚肾293T细胞（HEK293T细胞）中进行实验，以检测LH亚基的共定位和二聚化，并测量细胞内和细胞外LH浓度。
在患者基因组中发现了c.252C>G（p.F84L）和c.364G>A（p.G122S）的复合杂合突变。脉冲式GnRH治疗在促进青春期发育和排卵方面有效。免疫荧光染色后发现LHα亚基与两种突变β亚基共定位，免疫沉淀检测到LHα亚基与两种突变β亚基的二聚化。与野生型相比，细胞内LH浓度较高而细胞外LH浓度较低，表明LH存在分泌功能障碍。
LHB基因中c.252C>G（p.F84L）和c.364G>A（p.G122S）的复合杂合突变可能导致女性患者患CHH。这些突变不损害α亚基和β亚基的表达及二聚化，但会阻止LH的分泌。该研究扩展了我们对女性LHB基因突变临床表现的认识，并为这些患者提供了一种治疗方法。
