Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function

被引：164

作者：

Karaca, Ender ^{[1
,2
]}

Weitzer, Stefan ^{[2
]}

Pehlivan, Davut ^{[1
]}

Shiraishi, Hiroshi ^{[2
]}

Gogakos, Tasos ^{[3
]}

Hanada, Toshikatsu ^{[2
,20
]}

Jhangiani, Shalini N. ^{[4
]}

Wiszniewski, Wojciech ^{[1
]}

Withers, Marjorie ^{[1
]}

Campbell, Ian M. ^{[1
]}

Erdin, Serkan ^{[5
]}

Isikay, Sedat ^{[6
]}

Franco, Luis M. ^{[1
,7
]}

Gonzaga-Jauregui, Claudia ^{[1
]}

Gambin, Tomasz ^{[1
]}

Gelowani, Violet ^{[1
]}

Hunter, Jill V. ^{[8
]}

Yesil, Gozde ^{[9
]}

Koparir, Erkan ^{[10
]}

Yilmaz, Sarenur ^{[11
]}

Brown, Miguel ^{[3
]}

Briskin, Daniel ^{[3
]}

Hafner, Markus ^{[3
]}

Morozov, Pavel ^{[3
]}

Farazi, Thalia A. ^{[3
]}

Bernreuther, Christian ^{[12
]}

Glatzel, Markus ^{[12
]}

Trattnig, Siegfried ^{[13
]}

Friske, Joachim ^{[13
]}

Kronnerwetter, Claudia ^{[13
]}

Bainbridge, Matthew N. ^{[4
]}

Gezdirici, Alper ^{[10
]}

Seven, Mehmet ^{[10
]}

Muzny, Donna M. ^{[4
]}

Boerwinkle, Eric ^{[4
,14
]}

Ozen, Mustafa ^{[10
]}

Clausen, Tim ^{[15
]}

Tuschl, Thomas ^{[3
]}

Yuksel, Adnan ^{[10
]}

Hess, Andreas ^{[16
,17
]}

Gibbs, Richard A. ^{[1
,4
]}

Martinez, Javier ^{[2
]}

Penninger, Josef M. ^{[2
]}

Lupski, James R. ^{[1
,4
,18
,19
]}

机构：

[1] Baylor Coll Med, Dept Human Mol Genet, Dept Mol & Human Genet, Houston, TX 77030 USA

[2] Austrian Acad Sci, Inst Mol Biotechnol IMBA, A-1030 Vienna, Austria

[3] Rockefeller Univ, Howard Hughes Med Inst, Lab RNA Mol Biol, New York, NY 10065 USA

[4] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[5] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[6] Gaziantep Childrens Hosp, TR-27560 Gaziantep, Turkey

[7] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[8] Texas Childrens Hosp, Dept Pediat Radiol, Houston, TX 77030 USA

[9] Bezmialem Univ, Dept Med Genet, D-52425 Istanbul, Turkey

[10] Istanbul Univ, Cerrahpasa Med Sch, Dept Med Genet, D-52425 Istanbul, Turkey

[11] Istanbul Medeniyet Univ, Fac Med, Dept Med Genet, D-52425 Istanbul, Turkey

[12] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, D-20246 Hamburg, Germany

[13] Med Univ Vienna, MR Ctr Excellence, Dept Radiobiol, A-1090 Vienna, Austria

[14] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[15] Inst Mol Pathol, A-1030 Vienna, Austria

[16] Univ Erlangen Nurnberg, Inst Expt Pharmacol, D-91054 Erlangen, Germany

[17] Vienna BioCtr, CSF, A-1030 Vienna, Austria

[18] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[19] Texas Childrens Hosp, Houston, TX 77030 USA

[20] Kyoto Univ, Grad Sch Med, Med Innovat Ctr, Kyoto 6068507, Japan

来源：

CELL | 2014年 / 157卷 / 03期

关键词：

CAUSE PONTOCEREBELLAR HYPOPLASIA; SYNTHETASE MUTATIONS; PROTEIN FUNCTION; GENE; DISEASE; NEUROPATHY; COMPLEX;

D O I：

10.1016/j.cell.2014.02.058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 pretRNA 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 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.

引用

页码：636 / 650

页数：15

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