英國(guó)倫敦大學(xué)學(xué)院最近發(fā)布新聞公告稱(chēng),，包括該校科學(xué)家在內(nèi)的一國(guó)際研究小組發(fā)現(xiàn),，CDKN1C基因的特殊變異會(huì)導(dǎo)致IMAGe綜合征，而該基因的變異還與貝威二氏綜合征有關(guān),。同一基因的不同變異會(huì)導(dǎo)致截然相反的病癥，這一發(fā)現(xiàn)為科學(xué)家了解人類(lèi)生長(zhǎng)發(fā)育的奧秘提供了新的線索,。
IMAGe綜合征是一種極其罕見(jiàn)的發(fā)育異常疾病,，會(huì)影響生長(zhǎng)、腎上腺和性腺功能及骨骼肌發(fā)育,，導(dǎo)致胎兒體形及器官都小于正常水平,；而貝威二氏綜合征則與之截然相反，會(huì)使得胎兒超重,，內(nèi)臟肥大,。
過(guò)去有研究表明,，位于11號(hào)染色體上的CDKN1C基因在調(diào)節(jié)細(xì)胞生長(zhǎng)方面扮演著重要角色，該基因變異與貝威二氏綜合征有關(guān),。而由英美等國(guó)科學(xué)家組成的研究小組通過(guò)對(duì)阿根廷一個(gè)有IMAGe綜合征病史的家庭的DNA樣本分析發(fā)現(xiàn)，CDKN1C基因還與IMAGe綜合征有關(guān),。該基因的一種特殊變異，會(huì)限制胎兒發(fā)育，從而導(dǎo)致IMAGe綜合征,。
這一發(fā)現(xiàn)讓研究人員驚奇不已。“單一分子具有雙重功能,，是一種不常見(jiàn)的生理現(xiàn)象，而這兩種疾病還截然相反,。”世界上首個(gè)發(fā)現(xiàn)IMAGe綜合征的科學(xué)家埃里克·維萊恩教授說(shuō)，“這是一個(gè)巨大進(jìn)步,，我們可以通過(guò)基因測(cè)序來(lái)篩查變異，進(jìn)而更早地對(duì)IMAGe綜合征進(jìn)行診斷和醫(yī)療干預(yù),。”
事實(shí)上,，研究人員發(fā)現(xiàn)，IMAGe綜合征僅與母本遺傳的CDKN1C基因變異有關(guān),，如果僅有來(lái)自父親的變異基因副本,，孩子將不會(huì)患病。這種子代基因表達(dá)狀況取決于基因來(lái)自母本還是父本的現(xiàn)象,，被稱(chēng)作基因印記,，而相應(yīng)基因則稱(chēng)為印記基因。
論文作者之一,、英國(guó)倫敦大學(xué)學(xué)院的約翰·阿克曼博士說(shuō)：“我們的發(fā)現(xiàn)表明,，相同基因的不同變異會(huì)導(dǎo)致非常不同的結(jié)果,。這一發(fā)現(xiàn)不僅為我們提供了了解人類(lèi)生長(zhǎng)奧秘的線索，同時(shí)也有助于我們進(jìn)一步了解細(xì)胞生長(zhǎng),、分裂的過(guò)程，為腫瘤研究提供幫助,。”
相關(guān)研究成果發(fā)表在《自然遺傳學(xué)》Nature Genetics雜志上。（生物谷Bioon.com）
doi:10.1038/ng.2275
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Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome
Valerie A Arboleda, Hane Lee, Rahul Parnaik, Alice Fleming, Abhik Banerjee, Bruno Ferraz-de-Souza, Emmanuèle C Délot, Imilce A Rodriguez-Fernandez, Debora Braslavsky, Ignacio Bergadá, Esteban C Dell'Angelica, Stanley F Nelson, Julian A Martinez-Agosto, John C Achermann & Eric Vilain
IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences1. An identity-by-descent analysis in a family with IMAGe syndrome2 identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C (also known as P57KIP2) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression3, and we found that targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C, suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding, distinguishing them from the mutations of CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome4.
