Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing
Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing
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DOI：
10.1038/ncomms9718
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发表时间：
2015-11-01
影响因子：
16.6
通讯作者：
Scherer, Stephen W.
中科院分区：
文献类型：
--
作者：
Merico, Daniele;Roifman, Maian;Scherer, Stephen W.
罗夫曼综合征是一种罕见的先天性疾病，其特征是生长迟缓，认知迟缓，脊椎骨骺发育不良和抗体缺乏。在这里，我们利用Roifman综合征患者的全基因组测序来揭示复合杂合罕见变异，这些变异破坏RNU 4ATAC小核RNA基因的高度保守位置，RNU 4ATAC小核RNA基因是次要内含子剪接所必需的次要剪接体组分。靶向测序证实了来自四个无关家庭的六个病例中的等位基因分离。最近有报道称RNU 4ATAC罕见变体会导致小头畸形性骨发育异常原始侏儒症I型（MOPD 1），其表型与罗夫曼综合征不同。引人注目的是，所有六个Roifman综合征病例都有一个与MOPD 1相关结构元件重叠的变体，而另一个变体与先前未涉及疾病的高度保守结构元件重叠。RNA-seq分析证实了小内含子剪接的广泛和特异性缺陷。现有的等位基因频率数据表明，由RNU 4ATAC罕见变体引起的隐性遗传病可能比之前报道的更普遍。
Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.