Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6.
Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6.
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DOI：
10.1093/hmg/ddn381
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Shore, Paul
中科院分区：
文献类型：
--
作者：
Little, Hayley J.;Rorick, Nicholas K.;Su, Ling-I;Baldock, Clair;Malhotra, Saimon;Jowitt, Tom;Gakhar, Lokesh;Subramanian, Ramaswamy;Schutte, Brian C.;Dixon, Michael J.;Shore, Paul
唇裂和腭裂（CLP）是常见的疾病，作为综合征的一部分发生，其中唇和腭以外的结构受到影响，或者没有其他异常。货车德沃德综合征（VWS）和翼状胬肉综合征（PPS）是常染色体显性遗传疾病，其特征在于由干扰素调节因子6（IRF 6）突变引起的唇裂、CLP、唇凹、皮褶、并指和口腔粘连的组合。IRF 6属于转录因子家族，其共享高度保守的N-末端DNA结合结构域和不太保守的蛋白质结合结构域。迄今为止，突变分析表明广泛的基因型-表型相关性，其中IRF 6中发生的错义和无义突变可能导致VWS;相反，PPS引起的突变与DNA结合结构域高度相关，并且似乎优先影响预测与DNA直接相互作用的残基。然而，这种基因型-表型相关性是基于结构模型的分析，而不是基于IRF 6的DNA结合特性的研究。此外，蛋白质相互作用结构域中突变的影响尚未分析。在目前的研究中，我们已经确定了IRF 6结合的序列，并使用该序列来分析IRF 6的DNA结合结构域中VWS和PPS相关突变的影响。此外，我们已经证明，IRF 6的功能作为一个合作的转录激活因子和IRF 6的蛋白质相互作用结构域的突变破坏这种活动。
Cleft lip and cleft palate (CLP) are common disorders that occur either as part of a syndrome, where structures other than the lip and palate are affected, or in the absence of other anomalies. Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) are autosomal dominant disorders characterized by combinations of cleft lip, CLP, lip pits, skin-folds, syndactyly and oral adhesions which arise as the result of mutations in interferon regulatory factor 6 (IRF6). IRF6 belongs to a family of transcription factors that share a highly conserved N-terminal, DNA-binding domain and a less well-conserved protein-binding domain. To date, mutation analyses have suggested a broad genotype–phenotype correlation in which missense and nonsense mutations occurring throughout IRF6 may cause VWS; in contrast, PPS-causing mutations are highly associated with the DNA-binding domain, and appear to preferentially affect residues that are predicted to interact directly with the DNA. Nevertheless, this genotype–phenotype correlation is based on the analysis of structural models rather than on the investigation of the DNA-binding properties of IRF6. Moreover, the effects of mutations in the protein interaction domain have not been analysed. In the current investigation, we have determined the sequence to which IRF6 binds and used this sequence to analyse the effect of VWS- and PPS-associated mutations in the DNA-binding domain of IRF6. In addition, we have demonstrated that IRF6 functions as a co-operative transcriptional activator and that mutations in the protein interaction domain of IRF6 disrupt this activity.
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