Mutations in zinc finger 407 [ZNF407] cause a unique autosomal recessive cognitive impairment syndrome.
Mutations in zinc finger 407 [ZNF407] cause a unique autosomal recessive cognitive impairment syndrome.
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DOI：
10.1186/1750-1172-9-80
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发表时间：
2014-06-07
影响因子：
3.7
通讯作者：
El-Shanti H
中科院分区：
文献类型：
--
作者：
Kambouris M;Maroun RC;Ben-Omran T;Al-Sarraj Y;Errafii K;Ali R;Boulos H;Curmi PA;El-Shanti H
一个有血缘关系的阿拉伯家族受到一种明显的新型常染色体隐性遗传疾病的影响，其特征为认知障碍、发育不良、张力减退和畸形特征，包括双侧上睑下垂和内眦赘皮、滑液肌、面中部发育不全、嘴角下弯、上朱红色缘薄和耳突出、双侧第5指弯曲趾、双侧第4跖骨短和双侧膝关节活动受限。通过纯合性定位、候选基因突变筛查和单个受影响成员的全外显子组下一代测序来研究该家族，以确定致病基因和突变。用结构生物信息学方法对突变基因产物进行了研究。在ZNF407基因18q23处发现了一个破坏性的c.C5054G突变，该突变影响了进化上高度保守的氨基酸p.S1685W。丝氨酸到色氨酸的突变影响ZNF 407三种亚型中的两种，位于蛋白质的最后三分之一，在连接两个锌指结构域的连接肽中。该突变的结构分析显示，锁定两个指状物的相对空间位置的H键的破坏，导致接头的更高柔性，从而降低与靶DNA序列结合的可能性，基本上消除了下游结构域的功能，并干扰了胎儿脑发育期间ZNF 407控制下的各种基因的表达。ZNF 407是一种在脑发育中起重要作用的转录因子。当特定的和有限的纯合性区间存在，窝藏在近亲家庭中的致病基因，全外显子组测序的一个单一的受影响的个人是一个有效的方法，基因定位和突变鉴定。
A consanguineous Arab family is affected by an apparently novel autosomal recessive disorder characterized by cognitive impairment, failure-to-thrive, hypotonia and dysmorphic features including bilateral ptosis and epicanthic folds, synophrys, midface hypoplasia, downturned mouth corners, thin upper vermillion border and prominent ears, bilateral 5th finger camptodactyly, bilateral short 4th metatarsal bones, and limited knee mobility bilaterally. The family was studied by homozygosity mapping, candidate gene mutation screening and whole Exome Next Generation Sequencing of a single affected member to identify the offending gene and mutation. The mutated gene product was studied by structural bioinformatics methods. A damaging c.C5054G mutation affecting an evolutionary highly conserved amino acid p.S1685W was identified in the ZNF407 gene at 18q23. The Serine to Tryptophane mutation affects two of the three ZNF407 isoforms and is located in the last third of the protein, in a linker peptide adjoining two zinc-finger domains. Structural analyses of this mutation shows disruption of an H-bond that locks the relative spatial position of the two fingers, leading to a higher flexibility of the linker and thus to a decreased probability of binding to the target DNA sequence essentially eliminating the functionality of downstream domains and interfering with the expression of various genes under ZNF407 control during fetal brain development. ZNF407 is a transcription factor with an essential role in brain development. When specific and limited in number homozygosity intervals exist that harbor the offending gene in consanguineous families, Whole Exome Sequencing of a single affected individual is an efficient approach to gene mapping and mutation identification.
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影响因子：
14.9
作者：
Ramensky, V;Bork, P;Sunyaev, S
通讯作者：
Sunyaev, S
影响因子：
5.8
作者：
Peterson, Thomas A.;Adadey, Asa;Kann, Maricel G.
通讯作者：
Kann, Maricel G.
影响因子：
9.8
作者：
Lugtenberg, D;Yntema, HG;van Bokhoven, H
通讯作者：
van Bokhoven, H
影响因子：
4.5
作者：
Emerson RO;Thomas JH
通讯作者：
Thomas JH
DOI：
10.1016/j.bbadis.2012.11.009
发表时间：
2013-03-01
影响因子：
6.2
作者：
Ren, Cong-mian;Liang, Yan;Chen, Zheng
通讯作者：
Chen, Zheng