Nat Genetics:同一基因不同变异导致截然相反病症
导读 | <div id="region-column1and2-layout2">英国伦敦大学学院最近发布新闻公告称,包括该校科学家在内的一国际研究小组发现,CDKN1C基因的特殊变异会导致IMAGe综合征,而该基因的变异还与贝威二氏综合征有关。同一基因的不同变异会导致截然相反的病症,这一发现为科学家了解人类生长发育的奥秘提供了新的线索。</div>
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<div id="region-column1and2-layout2">英国伦敦大学学院最近发布新闻公告称,包括该校科学家在内的一国际研究小组发现,CDKN1C基因的特殊变异会导致IMAGe综合征,而该基因的变异还与贝威二氏综合征有关。同一基因的不同变异会导致截然相反的病症,这一发现为科学家了解人类生长发育的奥秘提供了新的线索。</div>
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IMAGe综合征是一种极其罕见的发育异常疾病,会影响生长、肾上腺和性腺功能及骨骼肌发育,导致胎儿体形及器官都小于正常水平;而贝威二氏综合征则与之截然相反,会使得胎儿超重,内脏肥大。
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过去有研究表明,位于11号染色体上的CDKN1C基因在调节细胞生长方面扮演着重要角色,该基因变异与贝威二氏综合征有关。而由英美等国科学家组成的研究小组通过对阿根廷一个有IMAGe综合征病史的家庭的DNA样本分析发现,CDKN1C基因还与IMAGe综合征有关。该基因的一种特殊变异,会限制胎儿发育,从而导致IMAGe综合征。
这一发现让研究人员惊奇不已。“单一分子具有双重功能,是一种不常见的生理现象,而这两种疾病还截然相反。”世界上首个发现IMAGe综合征的科学家埃里克·维莱恩教授说,“这是一个巨大进步,我们可以通过基因测序来筛查变异,进而更早地对IMAGe综合征进行诊断和医疗干预。”
事实上,研究人员发现,IMAGe综合征仅与母本遗传的CDKN1C基因变异有关,如果仅有来自父亲的变异基因副本,孩子将不会患病。这种子代基因表达状况取决于基因来自母本还是父本的现象,被称作基因印记,而相应基因则称为印记基因。
论文作者之一、英国伦敦大学学院的约翰·阿克曼博士说:“我们的发现表明,相同基因的不同变异会导致非常不同的结果。这一发现不仅为我们提供了了解人类生长奥秘的线索,同时也有助于我们进一步了解细胞生长、分裂的过程,为肿瘤研究提供帮助。”
相关研究成果发表在《自然遗传学》<em>Nature Genetics</em>杂志上。
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<a title="" href="http://dx.doi.org/doi:10.1038/ng.2275" target="_blank">doi:10.1038/ng.2275</a>
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<br/><strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome</strong><br/>
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.
<div><br/>来源:科技日报</div>
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IMAGe综合征是一种极其罕见的发育异常疾病,会影响生长、肾上腺和性腺功能及骨骼肌发育,导致胎儿体形及器官都小于正常水平;而贝威二氏综合征则与之截然相反,会使得胎儿超重,内脏肥大。
<!--more-->
过去有研究表明,位于11号染色体上的CDKN1C基因在调节细胞生长方面扮演着重要角色,该基因变异与贝威二氏综合征有关。而由英美等国科学家组成的研究小组通过对阿根廷一个有IMAGe综合征病史的家庭的DNA样本分析发现,CDKN1C基因还与IMAGe综合征有关。该基因的一种特殊变异,会限制胎儿发育,从而导致IMAGe综合征。
这一发现让研究人员惊奇不已。“单一分子具有双重功能,是一种不常见的生理现象,而这两种疾病还截然相反。”世界上首个发现IMAGe综合征的科学家埃里克·维莱恩教授说,“这是一个巨大进步,我们可以通过基因测序来筛查变异,进而更早地对IMAGe综合征进行诊断和医疗干预。”
事实上,研究人员发现,IMAGe综合征仅与母本遗传的CDKN1C基因变异有关,如果仅有来自父亲的变异基因副本,孩子将不会患病。这种子代基因表达状况取决于基因来自母本还是父本的现象,被称作基因印记,而相应基因则称为印记基因。
论文作者之一、英国伦敦大学学院的约翰·阿克曼博士说:“我们的发现表明,相同基因的不同变异会导致非常不同的结果。这一发现不仅为我们提供了了解人类生长奥秘的线索,同时也有助于我们进一步了解细胞生长、分裂的过程,为肿瘤研究提供帮助。”
相关研究成果发表在《自然遗传学》<em>Nature Genetics</em>杂志上。
<div id="ztload">
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201206/2012060120560928.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/ng.2275" target="_blank">doi:10.1038/ng.2275</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome</strong><br/>
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.
<div><br/>来源:科技日报</div>
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