Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism.
Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism.
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DOI：
10.1186/s13059-015-0779-x
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发表时间：
2015-09-28
期刊：
影响因子：
12.3
通讯作者：
Alkuraya FS
中科院分区：
文献类型：
--
作者：
Shaheen R;Abdel-Salam GM;Guy MP;Alomar R;Abdel-Hamid MS;Afifi HH;Ismail SI;Emam BA;Phizicky EM;Alkuraya FS
原始侏儒症是一种产前和产后极度生长缺陷的状态，其特点是显著的临床和遗传异质性。两个可能不相关的近亲家庭表现出一种明显的新形式的原始侏儒症，其中严重的生长缺陷伴随着明显的面部畸形，脑畸形（小头畸形，胼胝体发育不全和简化的旋转），以及严重的脑病伴癫痫发作。联合自合子/外显子分析显示，WDR4中一个新的错义突变可能是致病变异。WDR4是酵母Trm82的人类同源基因，Trm82是Trm8/Trm82全酶的重要组成部分，其作用是高度保守和特异性（m7G46）的tRNA甲基化。人类突变和相应的酵母突变导致特定tRNA物种的m7G46甲基化显著降低，这为与这种病变相关的原始侏儒症提供了潜在的机制，因为减少的m7G46修饰会导致酵母的生长缺陷表型。我们的研究扩大了原始侏儒症背后的生物学途径的数量，并增加了与异常tRNA修饰相关的不断增长的人类疾病列表。本文的在线版本（doi:10.1186/s13059-015-0779-x）包含补充材料，授权用户可以使用。
Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity. Two presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m7G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m7G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m7G46 modification causes a growth deficiency phenotype in yeast. Our study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification. The online version of this article (doi:10.1186/s13059-015-0779-x) contains supplementary material, which is available to authorized users.