染色体不安定と免疫不全症候群は,DNAメチルトランスフェラーゼ遺伝子の変異によって引き起こされる
G L Xu1, T H Bestor, D Bourc'his
1Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York 10032, USA.
Nature
|January 26, 2000
まとめ
免疫不全,セントロメア不安定,顔の異常 (ICF) 症候群は,DNAメチルトランスファーゼ3Bの変異と関連しています. この遺伝的疾患はゲノムメチル化パターンを破壊し,染色体の安定性と免疫機能に影響を及ぼします.
科学分野:
- 遺伝学 遺伝学とは
- エピジェネティクス エピジェネティクス
- 人間の病気 ヒトの病気
背景:
- ICF症候群は,免疫不全,セントロメア不安定,顔の異常によって特徴づけられる珍しい自己相性後退性疾患です.
- 患者はしばしば重度の感染症を経験し,免疫グロブリンレベルが低下したため,成人期前にそれらに屈します.
- 細胞遺伝学的異常には,ヘテロクロマチン延長,マルチ放射性染色体,および異常な核構造が含まれます.
研究 の 目的:
- ICF症候群の遺伝的根拠を調査する.
- 観察されたメチル化欠陥と臨床的特徴に起因する特定の遺伝子変異を特定する.
- ゲノム安定性と免疫機能の維持におけるDNAメチル化の役割を理解する.
主な方法:
- 血縁関係のないICF患者5人の遺伝子解析.
- DNAメチルトランスファーゼ3B (DNMT3B) 遺伝子の変異スクリーニング.
- 患者の組織におけるゲノムメチル化パターンの分析.
主要な成果:
- 5人のICF患者は,DNMT3B遺伝子の両方のアレルに変異があることが判明しました.
- ICF症候群は,衛星DNAにおけるサイトシンメチレーションのほぼ完全な欠如と関連しています.
- DNMT3Bの変異は,ヘテロクロマチン組織とゲノムメチル化パターンを破壊する.
結論:
- DNMT3B遺伝子の変異がICF症候群の原因である.
- DNMT3Bによる適切なサイトシンメチレーションは,ゲノム安定性および正常な免疫機能にとって極めて重要です.
- ICF症候群は,構成的ゲノムメチレーションに影響を与えるユニークな遺伝疾患を表しています.
関連する概念動画
01:08Nucleotide Excision Repair
Overview
01:39Mutations
Overview
02:46Genome Copying Errors
DNA replication is a well-evolved process that copies millions of base pairs with high fidelity during each cell division. Occasionally a wrong base or a long stretch of wrong bases may get added to the daughter strands. If the errors are left unchecked, cells might accumulate several mutations that might endanger their survival. Therefore, the copying errors are checked and repaired at three levels.
01:35Mutations
Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
01:38Nucleotide Excision Repair
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:30Spontaneous and Induced Mutations
Spontaneous mutations arise infrequently during DNA replication due to errors in the process. A key factor behind these errors is tautomeric shifts in nitrogenous bases, where bases transition from keto to enol forms or amino to imino forms. This shift can alter base-pairing rules, leading to mutations. Additionally, reactive oxygen species (ROS) arising from aerobic metabolism can damage DNA, resulting in depurination (loss of a purine base) or depyrimidination (loss of a pyrimidine base).