排骨综合征发现，与早期发展的关键事件联系

在三个孩子一个令人费解的多系统疾病的遗传分析，专家们发现了一种新的综合征，揭示关键的生物学过程，在人类的发展。该研究还提供了重要的信息，以帮助照顾者管理的障碍，并可能提供线索，最终治疗。

“这说明了一种综合征的总开关，控制其他基因在人类早期发展的一个非常重要的途径，”该研究的领导者伊恩D。 Krantz博士的个性化医学遗传中心在费城儿童医院的副主任（CHOP）。“将军”，医学遗传学家，是主治医师，CHOP综合人类的遗传程序。

“将军”是该研究的资深作者，今天在线发表在自然遗传学。他的合作研究的领导者是Katsuhiko shirahige，博士的分子和细胞生物学研究所，东京大学，也是第一作者耿介泉家机构。

被调查者命名为“障碍综合征”，其缩写代表一组受影响儿童的症状：认知障碍和粗相（面部特征）、心脏缺陷、肥胖、肺部受累、身材矮小和骨骼发育异常（异常骨发育）。

研究结果

中央研究发现是基因突变AFF4破坏一组称为超伸长复合体的蛋白质组（美国证券交易委员会）。美国证券交易委员会控制的转录过程中，脱氧核糖核酸被复制到核糖核酸，使基因表达在发育中的胚胎。这个生物过程的时间是严格规定的，所以任何干扰这个定时的东西都会干扰正常的发展。

“因为SEC参与细胞生物学的一个重要过程，它长期以来一直是研究的重点，特别是在癌症，说：”“将军”。“排骨综合征是一种人类发育性疾病在美国证券交易委员会的种系突变所导致的第一个例子。”

在胚胎中，胚系突变被传递给发育中的每个细胞，在多个器官和生物系统中有害的影响。突变AFF4基因产生突变的蛋白质，然后积累并导致级联的其他基因控制的异常AFF4。

“AFF4 has a critical role in human development, regulating so many other genes,” said Krantz。 “When it is mutated, it can damage the heart and skeleton, and lead to intellectual disability, among other effects。”

The current study sequenced the exomes (the protein-coding portions of DNA) of three unrelated children treated at CHOP for a complex developmental disorder。 All three patients had some symptoms similar to those found in patients with Cornelia deLange syndrome (CdLS), a rare multisystem disease long studied at CHOP。 Krantz led research that discovered the first causative gene for CdLS in 2004。

The research team’s DNA analysis and studies of gene expression patterns determined that the new syndrome is genetically distinct from CdLS, even while sharing some common molecular mechanisms。 Although only the three children in the study are known to definitely have CHOPS syndrome, Krantz expects diagnoses to increase with the dissemination of this discovery and the ongoing spread of faster, lower-cost gene-sequencing technology。

The research findings offer practical and emotional benefits for families, said Krantz。 Physicians may now order more appropriate tests to monitor and manage specific medical issues arising from CHOPS syndrome。 “This also means families and children can end their ‘diagnostic odyssey’ — the frustrating procession of tests and unsuccessful treatments that often occurs in trying to find an answer for families who have a child affected by a complex, undiagnosed disorder,” he added。

研究人员已经表明，排骨综合征是一种从头 condition — being caused by a new mutation arising in a single egg or sperm that went on to form the affected child, but not present in the patient’s parents。 Therefore, doctors can reassure parents that this illness is extremely unlikely to recur in any subsequent children。

Like many other rare genetic diseases, CHOPS syndrome does not yet have an effective treatment; physicians like Krantz can only manage the symptoms。 But the research team’s insight into the basic biology of this disorder may lay the groundwork for future treatments of this disease, and possibly others。

注意： See this blog posting from the CHOP Research Institute about the “medical odyssey” experienced by families of children with this syndrome。

The National Institutes of Health (grant HD052860) supported this study, as did the Cornelia deLange Syndrome Foundation and MEXT, a Japanese government agency。

“功能突变的生殖细胞增益AFF4造成一种新的综合征和功能链接超延伸复合物和黏合，”自然遗传学, published online March 2, 2015。

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