Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.
Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.
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DOI：
10.1038/ng.3762
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发表时间：
2017-03
期刊：
影响因子：
30.8
通讯作者：
Gleeson JG
中科院分区：
文献类型：
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作者：
Lardelli RM;Schaffer AE;Eggens VR;Zaki MS;Grainger S;Sathe S;Van Nostrand EL;Schlachetzki Z;Rosti B;Akizu N;Scott E;Silhavy JL;Heckman LD;Rosti RO;Dikoglu E;Gregor A;Guemez-Gamboa A;Musaev D;Mande R;Widjaja A;Shaw TL;Markmiller S;Marin-Valencia I;Davies JH;de Meirleir L;Kayserili H;Altunoglu U;Freckmann ML;Warwick L;Chitayat D;Blaser S;Çağlayan AO;Bilguvar K;Per H;Fagerberg C;Christesen HT;Kibaek M;Aldinger KA;Manchester D;Matsumoto N;Muramatsu K;Saitsu H;Shiina M;Ogata K;Foulds N;Dobyns WB;Chi NC;Traver D;Spaccini L;Bova SM;Gabriel SB;Gunel M;Valente EM;Nassogne MC;Bennett EJ;Yeo GW;Baas F;Lykke-Andersen J;Gleeson JG
脱腺苷酸酶最为人所知的是在mRNA衰变期间降解聚（A）尾。脱氢酶家族在整个进化过程中不断扩大，在哺乳动物中，由12种Mg 2+依赖性3 '端核糖核酸酶组成，其底物特异性大多未知。脑桥小脑发育不全7型（PCH 7）是一种以神经退行性变为特征的隐性遗传综合征，伴生殖器模糊（MIM%614969）。我们研究了12个患有PCH7的人类家族，发现了TOE1（NC_000001.11）中的双等位基因功能缺失突变，TOE1编码一种非常规去腺苷酸酶。Toe1-morphant斑马鱼表现出中脑和后脑变性，在体内模拟了类似PCH的结构缺陷。令人惊讶的是，我们发现TOE1与剪接体的不完全加工的小核（sn）RNA相关，这是负责前mRNA剪接。这些前snRNA含有3 '基因组编码的尾部，通常随后是转录后添加的腺苷。TOE1水平降低的人细胞积累3 '末端延伸的pre-snRNA，免疫分离的TOE1复合物足以使snRNA的3'末端成熟。我们的研究结果揭示了与snRNA成熟相关的神经退行性综合征的原因，并揭示了参与snRNA 3 '端加工的关键因素。
Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3’ end ribonucleases with mostly unknown substrate specificity. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration with ambiguous genitalia (MIM%614969). We studied 12 human families with PCH7, uncovering biallelic, loss of function mutations in TOE1 (NC_000001.11), which encodes an unconventional deadenylase. Toe1-morphant zebrafish displayed mid- and hind-brain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found TOE1 associated with incompletely processed small nuclear (sn)RNAs of the spliceosome, which is responsible for pre-mRNA splicing. These pre-snRNAs contained 3’ genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3’ end-extended pre-snRNAs, and immuno-isolated TOE1 complex was sufficient for 3’ end maturation of snRNAs. Our findings reveal the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in processing of snRNA 3’ ends.