Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.
Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.
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DOI：
10.1038/ng.2254
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发表时间：
2012-04-29
期刊：
影响因子：
30.8
通讯作者：
Jen, Joanna C.
中科院分区：
文献类型：
--
作者：
Wan, Jijun;Yourshaw, Michael;Mamsa, Hafsa;Rudnik-Schoeneborn, Sabine;Menezes, Manoj P.;Hong, Ji Eun;Leong, Derek W.;Senderek, Jan;Salman, Michael S.;Chitayat, David;Seeman, Pavel;von Moers, Arpad;Graul-Neumann, Luitgard;Kornberg, Andrew J.;Castro-Gago, Manuel;Sobrido, Maria-Jesus;Sanefuji, Masafumi;Shieh, Perry B.;Salamon, Noriko;Kim, Ronald C.;Vinters, Harry V.;Chen, Zugen;Zerres, Klaus;Ryan, Monique M.;Nelson, Stanley F.;Jen, Joanna C.
RNA外切体是在整个进化过程中保守的多亚基复合体，是处理、监视和周转各种编码和非编码RNA底物的主要细胞机制，对生存至关重要。通过外显子组测序，我们在四个患有婴儿脊髓运动神经元病、小脑萎缩、进行性小头畸形和严重的全球发育迟缓的兄弟姐妹中发现了外切体成分3(Exosome Component 3，EXOSC3)的隐性突变，这与桥小脑发育不全1型[PCH1；OMIM 607596]一致。我们在12个PCH1家系中另外8个发现了EXOSC3突变。在斑马鱼胚胎中，外显子3的吗啉敲除导致胚胎发育不良，大脑较小，运动能力差，这与人类的临床特征相似，并在很大程度上被共同注射的野生型而不是突变型外显子3所拯救。这些发现代表了导致人类疾病的RNA外切体基因的第一个例子，并进一步暗示了小脑和脊髓运动神经元发育不良和退化的RNA处理失调。
RNA exosomes are multi-subunit complexes conserved throughout evolution and emerging as the major cellular machinery for processing, surveillance, and turnover of a diverse spectrum of coding and non-coding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in exosome component 3 (EXOSC3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly, and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 [PCH1; OMIM 607596]. We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment with small brain and poor motility, reminiscent of human clinical features and largely rescued by coinjected wildtype but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome gene responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.
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影响因子：
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