Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.
Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.
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DOI：
10.1016/j.cell.2014.02.058
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发表时间：
2014-04-24
期刊：
影响因子：
64.5
通讯作者：
Lupski JR
中科院分区：
文献类型：
--
作者：
Karaca E;Weitzer S;Pehlivan D;Shiraishi H;Gogakos T;Hanada T;Jhangiani SN;Wiszniewski W;Withers M;Campbell IM;Erdin S;Isikay S;Franco LM;Gonzaga-Jauregui C;Gambin T;Gelowani V;Hunter JV;Yesil G;Koparir E;Yilmaz S;Brown M;Briskin D;Hafner M;Morozov P;Farazi TA;Bernreuther C;Glatzel M;Trattnig S;Friske J;Kronnerwetter C;Bainbridge MN;Gezdirici A;Seven M;Muzny DM;Boerwinkle E;Ozen M;Baylor Hopkins Center for Mendelian Genomics;Clausen T;Tuschl T;Yuksel A;Hess A;Gibbs RA;Martinez J;Penninger JM;Lupski JR
CLP1是一种参与tRNA剪接的RNA激酶。最近，CLP1激酶死亡的小鼠显示出神经肌肉疾病，运动神经元丢失和肌肉麻痹。人类基因组分析现在在五个不相关的家族中鉴定出CLP1纯合错义突变（p.R140H），导致CLP1与tRNA剪接内切酶（TSEN）复合物相互作用的丧失，大大降低了前tRNA切割活性，并积累了线性tRNA内含子。受影响的个体发展严重的运动感觉缺陷，皮质发育不全和小头畸形。携带激酶死亡的CLP 1的小鼠也表现出小头畸形和皮质脑体积减少，这是由于神经元祖细胞的细胞死亡增加，与皮质神经元数量减少有关。我们的数据阐明了一种新的神经系统综合征定义的CLP1突变，损害tRNA剪接。创始人突变纯合性的减少说明了罕见的疾病变异的重要性，并支持氏族基因组学假说。
CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a novel neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.
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