초록 열기/닫기 버튼
목적 : 조기난소부전은 난소발달기전을 이해하는 임상적 모델로, 조기난소부전의 유전적 원인을 밝힘으로써 난소분화 및 난포형성과정에 관련된 유전자를 알 수 있다. 조기난소부전은 40세 이전에 무월경과 성선자극호르몬이 증가되는 임상증후군으로 빈도는 약 1% 정도이다. 아직 조기난소부전의 기전은 밝혀지지 않았고, 터너 증후군, 자가면역질환, 항암제 치료, 방사선 치료 및 감염 등이 원인으로 알려져 있다. 많은 유전자가 조기난소부전의 후보 유전자로 제기되었고, 이환예에서 유전자들의 변이분석과 다른 원인을 조사하였으나, 조기난소부전의 약 60%에서 그 원인을 밝힐 수 없었고, 이들 중 대부분이 유전적 원인에 의한 것으로 보고되었다. 염색체 검사에 의해서 나타나지 않는 X 염색체의 결실이나 전좌 등과 아직 밝혀지지 않은 X 염색체상의 유전자의 변이가 조기난소부전의 원인이 될 수 있으며, 극비대칭의 X 염색체 불활성화 (highly skewed X chromosome inactivation)는 이런 이상을 가진 보인자에서 나타날 수 있다. 따라서 본 연구에서는 조기난소부전 환자에서 X 염색체의 결실이나 전좌 및 유전자 변이와 관련하여 극비대칭의 X 염색체 불활성화를 나타내는지를 조사하였다. 연구 방법 : 한국의 조기난소부전 환자 86명과 정상 대조군 83명 등 총 169명에서 극비대칭의 X 염색체 불활성화를 나타내는지를 알기 위하여 androgen receptor 유전자의 다형성을 이용하여 X 염색체 불활성화 비율을 측정하여 동일한 나이의 정상 대조군과 비교하였다. 결과 : 본 연구의 결과 한국의 조기난소부전 환자와 정상 대조군의 극비대칭의 X 염색체 불활성화 비율은 각각 10.5%, 4.1%로 조기난소부전 환자에서 극비대칭의 X 염색체 불활성화의 경향을 보였으나, 통계적 의의는 없었다 (p=0.2274). 극비대칭의 X 염색체 불활성화를 보인 한 명의 조기난소부전 환자에서 high resolution band karyotyping에서 X 염색체 단완의 terminal deletion이 발견되었다. 이는 X 염색체의 결실이나 전좌, 그리고 X 염색체상에 위치하는 조기난소부전과 관련된 유전자의 변이가 극비대칭의 X 염색체 불활성화를 보인 것으로 사료된다. 따라서 원인 불명의 조기난소부전 환자에서 극비대칭의 X 염색체 불활성화를 보일 경우 염색체 이상이나 유전자 변이의 간접적인 증거일 수 있다. 결론 : 모든 조기난소부전 환자에서 기초검사로 호르몬 검사, 자가항체검사, 염색체 검사 및 원인으로 알려진 유전자 변이분석 외에도 X 염색체 불활성화에 대한 선별검사가 필요할 것으로 사료된다.
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.
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.
키워드열기/닫기 버튼
Premature ovarian failure, Skewed X inactivation