Prader-Willi症候群
Prader-Willi症候群とは、父親由来の15番染色体長腕に微細欠失が起こった結果生じる隣接遺伝子症候群(微小欠失症候群)である。
隣接遺伝子症候群とは染色体に微細な欠失が起こった結果、隣接した複数の遺伝子が同時に障害されて生じる疾患を指す。
ちなみに医師国家試験問題を解くためだけならキーワードを上記の語呂で覚えるだけで十分である。この語呂を覚えていたらPrader-Willi症候群に関する問題はほぼ全部解けると思われるので安心して頂きたい。
102E19:低身長を伴う性腺機能低下症はどれか。
- Marfan症候群
- Cushing症候群
- Klinefelter症候群
- Prader-Willi症候群
- McCune-Albright症候群
解答:4.Prader-Willi症候群
Prader-Willi症候群では視床下部に障害が起こるので、それを原因とする成長ホルモン異常と性腺ホルモン異常により低身長を伴う性腺機能低下症となる。
上記の語呂でキーワードを覚えると良いと思われる。
109B15:隣接遺伝子症候群はどれか。
- Stos症候群
- Down症候群
- Turner症候群
- Klinefelter症候群
- Prader-Willi症候群
解答:Prader-Willi症候群
解説:隣接遺伝子症候群とは微細欠小欠失症候群とも呼ばれる。
国家試験レベルでは、染色体が欠失することで隣り合う複数の遺伝子が同時に障害されて起こる疾患の総称だという理解で十分だと思われる。
上記の語呂でキーワードとして覚えてしまうことをオススメする。
エピジェネティクスに関する内容はあくまで基礎医学を勉強していたり、遺伝学を勉強している方たちに向けたものである。
Prader-Willi症候群の症状
Prader-Willi症候群では15番染色体長腕が微細欠失するため、本来はその欠失部位に存在するはずのPrader-Willi症候群責任遺伝子群の機能が失われることで様々な症状が起こる。
新生児期は筋緊張低下による哺乳不良や呼吸中枢の機能障害による呼吸障害が問題となることが多い。
小児期は成長ホルモン異常による低身長や性腺ホルモン異常から生じる性腺機能低下症による外性器の低形成(停留精巣・矮小陰茎)が目立つ。しかし、女児の場合は外性器の低形成が見過ごされやすい。
他の症状として、満腹中枢の機能障害から過度に食事を摂取するようになることで肥満になったり、メラニン遺伝子の欠失から色白な皮膚となったりする。
また、精神発達遅滞も認める。
内分泌系の障害は視床下部(間脳)の機能障害としてまとめると理解しやすい。
エピジェネティクス
エピジェネティクスとはDNAの塩基配列によるものとは別に遺伝子発現を制御する仕組みを指したり、それを研究する学問領域のことを指す。
人間の細胞は元を辿ると一つの受精卵が細胞分裂してできたものなので、ゲノム(DNAの文字列で表される全ての遺伝情報)は全ての細胞で同一である。ゲノムの約30億塩基対の中には約22000個の遺伝子が含まれている。遺伝子とは特定のタンパク質を発現させる設計情報を含んだ領域を指す。
しかし、受精卵からは肝細胞や神経細胞や皮膚細胞などの全く異なった機能を持つ細胞が分化する。
これは例えば「肝細胞になる」ものは全部で22000個ある遺伝子のうち「肝細胞になる遺伝子」を選んで発現させているので、「肝細胞と呼ばれる」ようになったという事象が起こっているからである。
つまり、細胞ごとにゲノムから使う遺伝子や使わない遺伝子を選ぶことで様々な機能を持つ細胞に分化する仕組みが備わっているということになり、これはエピジェネティクスの例のうちの一つである。
エピジェネティクスは主に遺伝子発現を抑制させるDNAメチル化か遺伝子発現を促進するヒストンアセチル化といった化学修飾で行われることが分かっている。
エピジェネティクスの制御を行っている「エピジェネティクスコード」が存在するのではないかと考えられているが、未だ明らかとはなっていない。
例えば、「肝細胞になった」細胞には分化する前に「肝細胞になれ!」という「エピジェネティクスコード」が伝わったからこそ「肝細胞になった」のだと考えられるが、その分化を命令する「エピジェネティクスコード」がどのように伝わっているのかは明らかになっていないということである。
インプリンティング関連疾患
Prader-Willi症候群は父親由来の15番染色体長腕に微細欠失が起こった結果生じる隣接遺伝子症候群(微小欠失症候群)である。
これに非常に機序がよく似た疾患として、母親由来の15番染色体長腕に微細欠失が起こった結果生じる隣接遺伝子症候群(微小欠失症候群)であるAngelman症候群が存在する。
Prader-Willi症候群とAngelman症候群は15番染色体長腕という全く同じ部位が欠失するのだが、欠失する染色体が母親由来のものであるか父親由来のものであるかで2つの疾患に分かれるのである。
どうしてこのようなことが起こるのかを理解するためには、まずゲノムインプリンティング(ゲノム刷り込み)とインプリンティング遺伝子の存在を知ることが必要である。
ゲノムインプリンティングとインプリンティング遺伝子
通常、遺伝子は親の由来に関わらず父親由来だろうと母親由来だろうと同等に発現するのだが、インプリンティング遺伝子という例外が存在することが分かった。
インプリンティング遺伝子とはゲノムインプリンティング(ゲノム刷り込み)によって、「子世代になっても母親由来の遺伝子であるか父親由来の遺伝子であるかを記憶している」遺伝子である。
まるで自らがどちらかの親由来であるかを子世代になってからも覚えているかのように、母親由来のときと父親由来のときで子世代で発現する程度が異なるのである。
インプリンティング遺伝子には母親由来のときのみ発現する母性発現遺伝子と父親由来のときのみ発現する父性発現遺伝子がある。
子世代において自らが想定している由来と異なる場合にはエピジェネティックスな機構によりDNAメチル化されて発現しない。
つまり、父親由来の場合にのみ発現する父性発現遺伝子は母親由来の染色体ではDNAメチル化されてエピジェネティック機構により発現しない。また、母親由来の場合にのみ発現する母性発現遺伝子は父親由来の染色体ではDNAメチル化されてエピジェネティックスな機構により発現しないということである。
Prader-Willi症候群とAngelman症候群の違い
Prader-Willi症候群責任遺伝子、つまりその遺伝子が機能しなかった場合にPrader-Willi症候群を発症してしまう遺伝子は父性発現遺伝子である。子世代において父親由来のときにのみ発現して、母親由来のときはDNAメチル化されて発現しない。
Angelman症候群責任遺伝子、つまりその遺伝子が機能しなかった場合にAngelman症候群を発症してしまう遺伝子は母性発現遺伝子である。子世代において母親由来のときにのみ発現して、父親由来のときはDNAメチル化されて発現しない。
Prader-Willi症候群責任遺伝子とAngelman症候群責任遺伝子はどちらも第15染色体長腕に存在する。
しかし、父性発現遺伝子か母性発現遺伝子かという違いがあるので、父親由来の15番染色体長腕微細欠失が起こった場合にはPrader-Willi症候群を発症して母親由来の15番染色体長腕微細欠失が起こった場合にはAngelman症候群を発症するということになるのである。
Angelman症候群の症状
Angelman症候群の症状として重要なのはてんかんや笑い発作(誘因のない容易に引き起こされる笑いを認める)といった神経学的所見である。
Prader-Willi症候群と異なって内分泌系は障害されないため、内分泌学的な所見は認めない。
他には、下顎突出などの特徴的な顔貌を認めたり精神発達遅滞を認めることなどが重要である。
112D55:日齢12の新生児。呼吸障害のためNICUに入院中である。在胎37週、出生体重2,386g、身長47cmで帝王切開で出生した。筋緊張低下、色白な皮膚、矮小陰茎と停留精巣があり、哺乳障害を認める。FISH法にて15番染色体長腕に微細欠失を認める。
最も考えられるのはどれか。
- Werdnig-Hoffman症候群
- Prader-Willi症候群
- Klinefelter症候群
- Angelman症候群
- DiGeorge症候群
解答:2.Prader-Willi症候群
解説:FISH法にて15番染色体長腕に微細欠失を認めることからPrader-Willi症候群もしくはAngelman症候群のどちらかだと分かる。
上記の語呂で確認して頂きたいのだが、問題文の症状はPrader-Willi症候群の典型的な症状であることからPrader-Willi症候群が答えであると分かる。
Angelman症候群は内分泌学的な症状を認めないことがPrader-Willi症候群と異なる点であり、てんかんや笑い発作などが特徴的な症状となる。
このため、Prader-Willi症候群が新生児期から気づかれやすいことに比べると、Angelman症候群は新生児期に気づかれるということは少なく乳幼児期後半(3歳~7歳)にかけて診断されることが多い。
問題文では日齢12の新生児と書いてあるので、ここからPrader-Willi症候群であると判断してもよい。
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