Genetic Variations of GNRH1, GNRHR and GPR54 Genes in Korean Girls with Central Precocious Puberty
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목 적:중추성 성조숙증이란, 이차 성징의 징후가 동성에서의 평균 연령에 비해 2 표준편차 이상 어린 나이에 확인되는 경우로 정의된다. 중추성 성조숙증의 진행은 뇌하수체에서의 성선자극호르몬 방출호르몬(GnRH) 분비의 활성화에 의해 주도된다. 뇌하수체에서 발현되는 많은 유전자들이 사춘기의 시작과 진행에 중요한 역할을 하는 것으로 알려지고 있다. 본 연구에서는 한국인 중추성 성조숙증 여아를 대상으로, 이들 유전자 중에 GnRH와 이의 수용체를 암호화하는 GNRH1 및 GNRHR 유전자, kisspeptin의 수용체를 암호화하는 GPR54 유전자의 변이와 이의 임상적 의의를 확인하고자 하였다. 방 법:101명의 한국인 중추성 성조숙증 여아들이 환자군으로 모집되었으며, 대조군은 51명의 정상 사춘기 발달 과정을 거친 건강한 한국인 성인 여자들로 구성되었다. 환자군 및 대조군 모두를 대상으로 말초 혈액 백혈구에서 DNA를 추출하였으며, 각 유전자마다 특정 시발체를 사용하여 PCR한 후 그 산물을 이용하여 직접염기서열분석을 진행하였다. 환자군과 대조군 사이의 특정 염기서열 변이의 빈도 차이 및 환자군 내에서 특정 염기서열 보유 유무에 따른 여러 임상 변수의 차이를 통계 처리하여 분석하였다. 결 과:GNRH1, GNRHR 및 GPR54 유전자에서 네 종류의 다형성이 확인되었다. 이중에 GNRH1 유전자의 c.47G˃C와 GPR54 유전자의c.1091T˃A 변이는 이미 보고되어 있는 다형성이었으나, GNRH1 유전자의 c.196C˃T와 GNRHR 유전자의 c.546T˃C 변이는 과거 보고된 적이 없는 새로운 변이였다. 그러나 발견된 다형성들의 빈도는 환자군과 대조군에서 차이를 보이지 않았으며, 환자군 내에서도 특정 다형성의 유무에 따른 임상적 변수들의 차이를 확인할 수 없었다. 결 론:비록 본 연구의 대상 인원이 비교적 적기는 하지만, GNRH1, GNRHR 및 GPR54 유전자의 단순 다형성들은 사춘기의 시작 및 진행 과정에 직접적으로 크게 영향을 미치지는 않는 것으로 생각된다.
Abstract
Purpose:Central precocious puberty (CPP) is defined as any sign of secondary sexual maturation appears at an age lower than two standard deviations of the mean for the average age. This process is driven by activation of hypothalamic gonadotropin releasing hormone (GnRH) secretion. Many genes expressed in the hypothalamus have been identified to play an important role in the onset and the progression of puberty. In this study, the GNRH1, its receptor (GNRHR), and kisspeptin receptor (GPR54) genes were scanned to investigate sequence alterations and their distribution in Korean girls with CPP. Methods:One hundred and one Korean girls with CPP were recruited as the case group and 51 normal Korean women as the control group. The DNAs were extracted and amplified by polymerase chain reaction (PCR), and the products were sequenced directly. Statistical analyses were performed, and P values of ˂0.05 were considered significant. Results:Four polymorphisms were identified; however, no pathological mutation was found. Two of the polymorphisms were previously reported, c.47G˃C in GNRH1, and c.1091T˃A in GPR54. However, the other two (c.196C˃T in GNRH1 and c.546T˃C in GNRHR) were novel. There was no polymorphism that was significantly associated with early onset or rapid progression of puberty. Conclusion:Although the size of our study population was relatively small, simple genetic variations in GNRH1, GNRHR, and GPR54 genes are not likely to be a substantial factor directly associated with the onset and progression of puberty. (J Korean Soc Pediatr Endocrinol 2011;16:38-45)
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