디스트로핀 유전자에 새로이 발견된 불연속적 엑손 중복을 보이는 Duchenne형 근디스트로피 환자 5예
Novel Non-contiguous Duplications in the DMD Gene in Five Patients with Duchenne Muscular Dystrophy
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배경: 근디스트로피는 DMD 유전자의 돌연변이로 인해 발병하는 성염색체 열성 유전질환으로 심한 임상양상을 나타내는 DMD와 경미한 임상양상을 나타내는 BMD가 있다. DMD 유전자의 돌연변이를 검출하여 분석 결과를 바탕으로 해독틀법칙을 적용하면 DMD 또는 BMD로 진행하는 표현형 예측이 가능하다. 방법: DMD/BMD 진단을 위한 MLPA DMD test kit (MRC-Holland, The Netherlands)를 사용하여 검출한 돌연변이 양성 환자 총 88명 중 DMD 유전자의 불연속적 엑손 중복이 나타난 5예의 의무기록을 분석하였다. 비교적 드물게 발생하는 두 부위의 불연속적 엑손 중복 돌연변이 5예의 유전자검사 결과 및 임상 표현형을 이전 보고되었던 불연속적 엑손 중복 돌연변이 증례들과 비교 분석하였다. 결과: 본 연구에서 기존 보고된 바 없는 세 가지 형태의 불연속적 엑손 중복 돌연변이가 관찰되었으며, 각각 DMD 유전자 엑손 2-7 부위와 엑손 45-51 부위, 엑손 5-37 부위와 엑손 50-59 부위, 엑손 52-53 부위와 엑손 56-61 부위의 중복이었다. 본 연구에서 제시된 DMD 유전자의 불연속적 엑손 중복 5예는 모두 DMD 표현형을 나타냈다. 결론: DMD 유전자의 불연속적 엑손 중복 돌연변이에서 각각의 중복이 상호 복합적으로 작용하여 유전자 발현에 영향을 주기 때문에 일반적인 해독틀법칙에 의한 표현형 예측이 어렵다. 대부분의 불연속적 엑손 중복 돌연변이는 DMD 표현형을 나타냈으며, 이에 대한 분별력 있는 해독틀법칙 적용이 필요하다. 본 증례 고찰은 근디스트로피의 유전형-표현형 예측 또는 치료 목적의 디스트로핀 개발과 관련한 기전 연구에 있어 중요할 것으로 생각된다.
Abstract
Background: Muscular dystrophy is an X-linked recessive disorder caused by mutations in the DMD gene. Muscular dystrophy is classified into 2 types; Duchenne muscular dystrophy (DMD), which has severe clinical symptoms, and Becker muscular dystrophy (BMD), which has much milder clinical symptoms. Phenotypic progression to either DMD or BMD can be predicted by analyzing mutations in DMD by using the reading frame rule. Methods: Of 88 patients with mutations in DMD, which were detected using Multiplex Ligation-dependent Probe Amplification DMD test kit (MRC-Holland, The Netherlands), medical records of 5 patients with non-contiguous duplications were reviewed. These rare non-contiguous duplications in DMD were compared with those reported previously. Results: We identified 3 novel non-contiguous duplications in DMD that included exons 2-7 and 45-51, exons 5-37 and 50-59, and exons 52-53 and 56-61. The 5 patients with these non-contiguous duplications showed the phenotypic features of DMD. Especially, duplication of exons 52-53 and 56-61 was observed in a family, i.e., 2 DMD-affected brothers and their carrier mother. Conclusions: Prediction of phenotypes associated with complex non-contiguous duplications by using the reading frame rule is difficult because the duplications affect the expression of DMD together. Because most patients with non-contiguous duplications showed the phenotypic features of DMD, the reading frame rule should be interpreted cautiously. This study provides important insights on the non-contiguous duplications in DMD for understanding genotype-phenotype correlations and for developing dystrophin for therapeutic purposes.
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