Lixia Zhu1, Nan Xiao2, Tao Zhang1, Pingping Kong3, Bei Xu1, Zishui Fang1, Lei Jin4. 1. Reproductive Medicine Center, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, 1095 JieFang Avenue, Wuhan, 430030, People's Republic of China. 2. Department of Center for Reproductive Medicine, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, 300100, People's Republic of China. 3. The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China. 4. Reproductive Medicine Center, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, 1095 JieFang Avenue, Wuhan, 430030, People's Republic of China. leijintongjih@qq.com.
Abstract
OBJECTIVE: To characterize the clinical features of a female patient with isolated follicle-stimulating hormone (FSH) deficiency and to investigate the underlying mechanisms of FSH inactivation. METHODS: The proband was a 29-year-old woman with primary amenorrhea, impaired pubertal development, and infertility. Subsequently, reproductive endocrine was screened. DNA sequencing was conducted for the identification of FSHβ mutation. RT-PCR, western blots, in vitro immunometric assay, and bioassay were performed to confirm the impact of the mutation on FSH expression and biological activity. Molecular model consisting of FSHα and mutant FSHβ subunit was built for the structural analysis of FSH protein. RESULTS: The evaluation of reproductive endocrine revealed undetectable basal and GnRH-stimulated serum FSH. Sequencing of the FSHβ gene identified a homozygous nonsense mutation at codon 97 (Arg97X). RT-PCR and western blot analysis revealed the mutation Arg97X did not affect FSHβ mRNA and protein expression. But in vitro immunometric assay and bioassay demonstrated the production of normal bioactive FSH protein was disturbed by the mutation Arg97X. Structural analysis showed the surface structure of the resulting mutant FSH presented with lock-and-key, mosaic binding pattern, while the native structure was an encircling binding mode. CONCLUSION: The mutation Arg97X could disturb structural stability of the resulting FSH protein consisting of FSHα and mutant FSHβ subunit, which may lead to FSH deficiency.
OBJECTIVE: To characterize the clinical features of a female patient with isolated follicle-stimulating hormone (FSH) deficiency and to investigate the underlying mechanisms of FSH inactivation. METHODS: The proband was a 29-year-old woman with primary amenorrhea, impaired pubertal development, and infertility. Subsequently, reproductive endocrine was screened. DNA sequencing was conducted for the identification of FSHβ mutation. RT-PCR, western blots, in vitro immunometric assay, and bioassay were performed to confirm the impact of the mutation on FSH expression and biological activity. Molecular model consisting of FSHα and mutant FSHβ subunit was built for the structural analysis of FSH protein. RESULTS: The evaluation of reproductive endocrine revealed undetectable basal and GnRH-stimulated serum FSH. Sequencing of the FSHβ gene identified a homozygous nonsense mutation at codon 97 (Arg97X). RT-PCR and western blot analysis revealed the mutation Arg97X did not affect FSHβ mRNA and protein expression. But in vitro immunometric assay and bioassay demonstrated the production of normal bioactive FSH protein was disturbed by the mutation Arg97X. Structural analysis showed the surface structure of the resulting mutant FSH presented with lock-and-key, mosaic binding pattern, while the native structure was an encircling binding mode. CONCLUSION: The mutation Arg97X could disturb structural stability of the resulting FSH protein consisting of FSHα and mutant FSHβ subunit, which may lead to FSH deficiency.
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