Publication: Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function
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Karaca, Ender
Weitzer, Stefan
Pehlivan, Davut
Shiraishi, Hiroshi
Gogakos, Tasos
Hanada, Toshikatsu
Jhangiani, Shalini N.
Wiszniewski, Wojciech
Withers, Marjorie
Campbell, Ian M.
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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 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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Citation
Karaca E., Weitzer S., Pehlivan D., Shiraishi H., Gogakos T., Hanada T., Jhangiani S. N. , Wiszniewski W., Withers M., Campbell I. M. , et al., -Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function-, CELL, cilt.157, ss.636-650, 2014