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한국 소아 뇌하수체기능저하증 환자에서의 PROP1 유전자 분석에 관한 연구

PROP1 Gene Analysis in Korean Children with Hypopituitarism

황일태|황진순|이효성
대한소아내분비학회 (Korean Society Of Pediatric Endocrinology)|2009.06|Annals of Pediatric Endocrinology & Metabolism|제14권 제1호|pp. 52-59

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키워드

PolymorphismHypopituitarismPROP1
주제분류소아과학

초록

목 적:PROP1 유전자의 돌연변이는 성장호르몬, 갑상샘자극호르몬, 황체화호르몬과 여포자극호르몬, 프로락틴, 부신피질자극호르몬의 결핍을 특징으로 하는 복합 뇌하수체기능저하증, 또는 드물게 단독 성장호르몬결핍증을 일으킨다. 본 연구는 한국 소아 뇌하수체기능저하증 환아에서 PROP1 유전자를 분석하고자 하였다. 방 법:아주대병원 소아청소년과에서 선천성 뇌하수체기능저하증으로 진단받은 12명의 환아를 대상으로 하였다. 뇌하수체기능저하증의 임상 양상은 단독 성장호르몬결핍증과 복합 뇌하수체기능저하증을 포함하였다. 의무 기록을 열람하여 내분비학적, 신경방사선학적인 임상 정보를 후향적으로 조사하였고, 환아로부터 정맥혈을 채취하여 DNA를 추출하였으며, PCR 방법을 이용하여 PROP1 유전자를 검사하였다. PCR 산물은 직접 서열 분석을 하였다. 결 과:뇌하수체 자기공명영상에서 9명의 환아들이 이상 소견을 보였고, 3명의 환아들이 정상 소견을 보였다. 내분비학적으로는 7명에서 단독 성장호르몬결핍증, 5명에서 복합 뇌하수체기능저하증이었는데, 이들 중 성장호르몬결핍증과 동반된 황체화호르몬, 여포자극호르몬 결핍증이 3명, 성장호르몬에 동반된 갑상샘자극호르몬 결핍증과 부신피질자극호르몬 결핍증이 2명이었다. 본 연구에서는 PROP1 유전자의 돌연변이를 발견할 수 없었다. 그러나, 3개의 알려진 다형성을 발견할 수 있었는데, 총 24개의 대립 유전자(allele)들 중에서, 엑손 1번에서 27T→C (Ala9Ala)와 이것과 연관된 IVS1＋3A→G을 25%(4명)에서 발견하였고, 엑손 3번에서 242G→A (Ala142Thr)을 4% (1명)에서 발견하였다. 결 론:본 연구는 PROP1 유전자의 돌연변이가 산발적으로 발생하는 뇌하수체기능저하증 환자에서는 드물게 발견된다는 선행 연구들의 보고들과 일치한다. 한국의 환자들에서 돌연변이가 적은 이유는 다른 밝혀지지 않은 유전자가 관여하기 때문일 수 있고, 인종적인 차이가 있을 가능성이 있다. 그러나, 본 연구의 환자수가 적어서 더 많은 한국 환자들의 PROP1 유전자 분석을 통해 질환과의 연관성을 밝히는 것이 필요하겠다.

Abstract

Purpose:Mutations of the PROP1 (Prophet of PIT1) gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of growth hormone (GH), thyroid stimulating hormone (TSH), luteinizing hormone (LH)/follicle stimulating hormone (FSH), prolactin (PRL) and adrenocorticotropic hormone (ACTH). We studied the PROP1 mutations in Korean children with hypopituitarism. Methods:Twelve patients with congenital hypopituitarism were recruited from the Ajou University Hospital, Korea. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to CPHD. Clinical data, including endocrine and neuroradiological data were obtained from the medical records, and the DNA was collected and screened for mutations within PROP1 using polymerase chain reaction (PCR). The PCR products were sequenced directly. Results:Nine patients had abnormal pituitary gland and three patients showed normal pituitary gland in magnetic resonance imaging (MRI). Endocrinologically, seven patients had IGHD and five had CPHD. Three of CPHD had GHD and hypogonadotrophic hypogonadism and the other two had GHD, central hypothyroidism, and ACTH deficiency. We identified no mutations in the PROP1 gene. However, three known polymorphisms were identified: The 27T→C (Ala9Ala) and the associated IVS1+3A→G in exon 1 were found in 25% of patient alleles sequenced. The 424G→A (Ala142Thr) in exon 3 change was identified in 4% of those sequenced. Conclusion:This study corresponds to the previous reports that PROP1 mutations are rare in sporadic cases of CPHD. The low mutation frequency in Korean patients may be due to ethnic-specificity or other candidate genes causing this disease. It is necessary to study PROP1 gene and the involved genes in more Korean patients.

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