2012年8月13日 訊 /生物谷BIOON/ --遺傳學(xué)研究人員鑒定出一個(gè)關(guān)鍵性基因,，當(dāng)它發(fā)生突變時(shí),，導(dǎo)致一種罕見的被稱作狄蘭氏綜合癥(Cornelia deLange syndrome, CdLS)的多系統(tǒng)疾病發(fā)生,。通過揭示HDAC8基因發(fā)生突變?nèi)绾纹茐目刂苹虮磉_(dá)和細(xì)胞分裂的蛋白的功能,，這項(xiàng)研究有助于人們認(rèn)識這種由于早期發(fā)育受損而導(dǎo)致智力障礙,、肢體畸形和其他殘疾的疾病,。
在此之前,，研究人員在2004年報(bào)道NIPBL基因發(fā)生突變是CdLS的主要原因,，大約占這種疾病的60%。2007年,，他們又描述了兩個(gè)新的基因SMC1A和SMC3,。
在這項(xiàng)研究中，研究人員重點(diǎn)關(guān)注黏連蛋白復(fù)合物(cohesin complex)：它是由一組蛋白組成的,，能夠形成一種手鏈狀結(jié)構(gòu),，包圍著一對被稱作姊妹染色單體的染色體。黏連蛋白有兩種作用,。它讓姊妹染色單體在細(xì)胞分類期間保持在一起,，同時(shí)它還允許正常的轉(zhuǎn)錄產(chǎn)生。論文第一作者M(jìn)atthew A. Deardorff博士說,，破壞黏連蛋白正常功能的突變能夠干擾正常的人類發(fā)育,。
在當(dāng)前這項(xiàng)研究中，研究人員研究了乙?；腿ヒ阴,；瘜︷みB蛋白功能的影響。在正常條件下,，去乙?；兄诨厥绽灭みB蛋白，從而使得它在連續(xù)幾輪細(xì)胞分裂期間能夠被細(xì)胞使用,。他們發(fā)現(xiàn)HDAC8基因發(fā)生突變破壞細(xì)胞對黏連蛋白的正常循環(huán)利用,。
這種基因發(fā)生突變導(dǎo)致HDAC8蛋白活性丟失，因而降低細(xì)胞獲得循環(huán)利用黏連蛋白的數(shù)量從而不能讓它正確地調(diào)節(jié)基因轉(zhuǎn)錄,。研究人員提示著,，這會(huì)傷害正常的胚胎發(fā)育和導(dǎo)致CdLS產(chǎn)生。
研究人員在細(xì)胞培養(yǎng)物中證實(shí)HDAC8發(fā)生突變導(dǎo)致黏連蛋白結(jié)合到基因上的能力下降,，這類似于細(xì)胞中NIPBL基因缺乏時(shí)觀察到的情形,。他們也鑒定出大約5%的CdLS患者發(fā)生HDAC8突變。
Deardorff說,，通過提供CdLS中基因缺陷的詳細(xì)信息,，這項(xiàng)當(dāng)前的研究提示著人們在未來開發(fā)出治療這種遺傳性疾病的方法,。(生物谷Bioon.com)
本文編譯自Cornelia deLange syndrome: Mutations disrupt cellular recycling and cause childhood genetic disease
doi: 10.1038/nature11316
PMC:
PMID:
HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle
Matthew A. Deardorff, Masashige Bando, Ryuichiro Nakato et al
Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL1, 2 for nearly 60% of individuals with classical CdLS3, 4, 5, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands6, 7. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion8 and also has key roles in gene regulation9. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin10, 11, 12, 13, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase14, 15, 16. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.
