| Literature DB >> 24766809 |
Ender Karaca1, Stefan Weitzer2, Davut Pehlivan1, Hiroshi Shiraishi2, Tasos Gogakos3, Toshikatsu Hanada4, Shalini N Jhangiani5, Wojciech Wiszniewski1, Marjorie Withers1, Ian M Campbell1, Serkan Erdin6, Sedat Isikay7, Luis M Franco8, Claudia Gonzaga-Jauregui1, Tomasz Gambin1, Violet Gelowani1, Jill V Hunter9, Gozde Yesil10, Erkan Koparir11, Sarenur Yilmaz12, Miguel Brown3, Daniel Briskin3, Markus Hafner3, Pavel Morozov3, Thalia A Farazi3, Christian Bernreuther13, Markus Glatzel13, Siegfried Trattnig14, Joachim Friske14, Claudia Kronnerwetter14, Matthew N Bainbridge5, Alper Gezdirici11, Mehmet Seven11, Donna M Muzny5, Eric Boerwinkle15, Mustafa Ozen11, Tim Clausen16, Thomas Tuschl3, Adnan Yuksel11, Andreas Hess17, Richard A Gibbs18, Javier Martinez19, Josef M Penninger20, James R Lupski21.
Abstract
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 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.Entities:
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Year: 2014 PMID： 24766809 PMCID： PMC4146440 DOI： 10.1016/j.cell.2014.02.058
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582