ZNF674:: A new Kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation
ZNF674:: A new Kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation
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DOI：
10.1086/500306
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发表时间：
2006-02-01
影响因子：
9.8
通讯作者：
van Bokhoven, H
中科院分区：
文献类型：
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作者：
Lugtenberg, D;Yntema, HG;van Bokhoven, H
基于阵列的比较基因组杂交已被证明是成功的，在涉及精神发育迟滞的疾病的遗传缺陷的鉴定。在这里，我们研究了一个有学习障碍、视网膜营养不良和身材矮小的病人。家族史提示X连锁邻接基因综合征。全覆盖的X染色体细菌人工染色体阵列的杂交显示，在Xp11.3，其中含有RP 2，SLC 9A 7，CHST 7，和两个假设的锌指基因，ZNF 673和ZNF 674类似的1 Mb的缺失。这些基因在28个非综合征性X连锁精神发育迟滞（XLMR）家族中进行了分析，显示与Xp11.3连锁;分析显示一个家族的ZNF 674编码序列中存在无义突变p.E118X。这种突变预计会导致一个截短的蛋白质含有Kruppel相关的框结构域，但缺乏锌指结构域，这是至关重要的DNA结合。我们描述了完整的ZNF 674基因结构，随后通过直接测序检测了另外306例XLMR患者的突变。两个氨基酸取代，p.T343M和p.P412L，在未受影响的个体中没有发现。412位的脯氨酸在物种之间是保守的，并且通过分子模拟预测，其降低了ZNF 674的DNA结合特性。p.T343M转换可能是一种多态性，因为黑猩猩的同源ZNF 674基因在该位置有一个甲硫氨酸。ZNF 674属于Xp 11中7个高度相关的锌指基因簇，其中两个（ZNF 41和ZNF 81）先前与XLMR有关。ZNF 674作为该簇中第三个XLMR基因的鉴定可能表明这些锌指基因对人类认知功能至关重要的共同作用。
Array-based comparative genomic hybridization has proven to be successful in the identification of genetic defects in disorders involving mental retardation. Here, we studied a patient with learning disabilities, retinal dystrophy, and short stature. The family history was suggestive of an X-linked contiguous gene syndrome. Hybridization of full-coverage X-chromosomal bacterial artificial chromosome arrays revealed a deletion of similar to 1Mb in Xp11.3, which harbors RP2, SLC9A7, CHST7, and two hypothetical zinc-finger genes, ZNF673 and ZNF674. These genes were analyzed in 28 families with nonsyndromic X-linked mental retardation ( XLMR) that show linkage to Xp11.3; the analysis revealed a nonsense mutation, p.E118X, in the coding sequence of ZNF674 in one family. This mutation is predicted to result in a truncated protein containing the Kruppel-associated box domains but lacking the zinc-finger domains, which are crucial for DNA binding. We characterized the complete ZNF674 gene structure and subsequently tested an additional 306 patients with XLMR for mutations by direct sequencing. Two amino acid substitutions, p.T343M and p.P412L, were identified that were not found in unaffected individuals. The proline at position 412 is conserved between species and is predicted by molecular modeling to reduce the DNA-binding properties of ZNF674. The p.T343M transition is probably a polymorphism, because the homologous ZNF674 gene in chimpanzee has a methionine at that position. ZNF674 belongs to a cluster of seven highly related zinc-finger genes in Xp11, two of which ( ZNF41 and ZNF81) were implicated previously in XLMR. Identification of ZNF674 as the third XLMR gene in this cluster may indicate a common role for these zinc-finger genes that is crucial to human cognitive functioning.