The clinical models for studying ovary-determining genes may be premature ovarian failure (POF). POF is a condition causing amenorrhea, hypoestrogenism, and elevated gonadotropins in women under 40 years old. FSH receptor, LH receptor, inhibin, GDF-9 (growth differentiation factor-9), BMP-15 (bone morphogenetic protein-15), DIAPH2 (diaphanous gene) and XPNPEP2 (X-prolyl aminopeptidase) genes were proposed as a possible candidate gene, but until recently, only mutations in FSH receptor, LH receptor and inhibin genes have been identified in POF patients. Therefore mutation screening of another POF gene necessary to reveal the principal causative genes of POF. OBJECTIVE: The present study was performed to analyze the mutation of GDF-9 gene in Korean patient with POF and to investigate whether mutation of these gene is a likely main cause of POF. METHODS: Eighty-six women with POF were studied and thirty-six normal women were enrolled as control. Mutation screening of these genes were performed by denaturing HPLC and were confirmed by automatic sequencing. RESULTS: Three different mutations of GDF-9 gene were identified in Korean women with POF; Arg3Cys mutation in one patient, Leu40Val mutation in one patient, Asp57Tyr mutation in 10 patients and 5 normal controls. Arg3Cys mutation and Leu40Val mutation were likely cause of disease. Frequencies of Arg3Cys mutation and Leu40Val mutation were 1.2%, respectively. Asp57Tyr mutation was common polymorphism in Korean women. All mutations was a novel mutation found in the present study. CONCLUSION: POF was resulted by mutations of GDF-9 gene, but mutations of GDF-9 gene are not likely main causes of POF because of low frequency of mutations.
Adult ; Amenorrhea ; Bone Morphogenetic Protein 15 ; Chromatography, High Pressure Liquid ; Female ; Gonadotropins ; Growth Differentiation Factor 9 ; Humans ; Inhibins ; Mass Screening ; Primary Ovarian Insufficiency* ; Receptors, FSH ; Receptors, LH

OBJECTIVE: Premature ovarian failure (POF) is a highly heterogenous condition, and its etiology remains unknown in approximately two-thirds of cases. POF can be caused by Turner syndrome, genetic disease, iatrogenic agents such as chemotherapy and radiotherapy, infection and autoimmune disease. X chromosome inactivation is the random process in females during early embryogenesis to achieve dosage compensation with males. But skewed X chromosome inactivation occurs in the female carriers, secondary to cell-autonomous selection against cells in which the abnormal X chromosome is active. Highly skewed X chromosome inactivation is likely to occur in POF which caused by subcytogenetic X chromosome deletion or translocation and X-linked gene mutation. The present study was performed to investigate whether highly skewed inactivation of X chromosome is observed in POF. METHODS: Eighty-six women with premature ovarian failure were studied and eighty-three normal women were enrolled as a control group. X chromosome inactivation pattern were determined by studying methylation pattern of androgen receptor gene. RESULTS: Seventy-six of the 86 POF patients were informative for X chromosome inactivation assay, 8 (10.5%) of them showed highly skewed X chromosome inactivation. In the age matched control group, 3 (4.1%) out of the 74 subjects showed highly skewed X chromosome inactivation. However, this finding is not statistically significant (p=0.2274). Among highly skewed X inactivation, one case of premature ovarian failure revealed 46,XX,del(X)(p21) by high resolution band karyotyping. Therefore highly skewed X inactivation can provide clues to evaluate the causes in POF. CONCLUSION: This study suggests that screening of skewed X chromosome inactivation for the POF will be useful to detect subcytogenetic X chromosome deletion or translocation and X-linked gene mutation associated with POF.
Autoimmune Diseases ; Compensation and Redress ; Drug Therapy ; Embryonic Development ; Female ; Genes, X-Linked ; Humans ; Iatrogenic Disease ; Karyotyping ; Male ; Mass Screening ; Methylation ; Pregnancy ; Primary Ovarian Insufficiency* ; Radiotherapy ; Receptors, Androgen ; Turner Syndrome ; X Chromosome Inactivation* ; X Chromosome*