Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly
Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly
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DOI：
10.1111/cge.12884
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发表时间：
2017-05-01
影响因子：
3.5
通讯作者：
Chitayat, D.
中科院分区：
文献类型：
--
作者：
Kernohan, K. D.;McBride, A.;Chitayat, D.
翻译后蛋白质修饰以指数方式扩展由人类基因组编码的蛋白质的功能互补。一种这样的修饰是将甲基共价添加到精氨酸或赖氨酸残基，其用于调节蛋白质组的大部分。精氨酸和赖氨酸甲基化分别由蛋白质精氨酸甲基转移酶（PRMT）和蛋白质赖氨酸甲基转移酶蛋白（PKMT）催化;每种甲基转移酶都有一组特定的靶底物。在这里，我们报告了一名男性严重的智力残疾，面部畸形，小头畸形，身材矮小，短指，隐睾和癫痫谁被发现有一个纯合的15，309 bp的缺失，包括PRMT 7的转录起始位点，我们证实是一个功能无效等位基因。我们发现，患者细胞的蛋白质精氨酸甲基化水平降低，受影响的蛋白质包括必需的组蛋白H2 B和H4。最后，我们证明了患者细胞改变了Wnt信号传导，这可能导致了骨骼异常。我们的研究结果证实了PRMT 7最近的疾病关联，扩大了这种疾病的表型表现，并提供了对这种新疾病的分子发病机制的见解。
Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition.