Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function

Ender Karaca, Stefan Weitzer, Davut Pehlivan, Hiroshi Shiraishi, Tasos Gogakos, Toshikatsu Hanada, Shalini N. Jhangiani, Wojciech Wiszniewski, Marjorie Withers, Ian M. Campbell, Serkan Erdin, Sedat Isikay, Luis M. Franco, Claudia Gonzaga-Jauregui, Tomasz Gambin, Violet Gelowani, Jill V. Hunter, Gozde Yesil, Erkan Koparir, Sarenur Yilmaz & 24 others Miguel Brown, Daniel Briskin, Markus Hafner, Pavel Morozov, Thalia A. Farazi, Christian Bernreuther, Markus Glatzel, Siegfried Trattnig, Joachim Friske, Claudia Kronnerwetter, Matthew N. Bainbridge, Alper Gezdirici, Mehmet Seven, Donna M. Muzny, Eric Boerwinkle, Mustafa Ozen, Tim Clausen, Thomas Tuschl, Adnan Yuksel, Andreas Hess, Richard A. Gibbs, Javier Martinez, Josef M. Penninger, James R. Lupski

Research output: Contribution to journalArticle

85 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)636-650
Number of pages15
JournalCell
Volume157
Issue number3
DOIs
StatePublished - Apr 24 2014
Externally publishedYes

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Peripheral Nervous System
Neurology
Transfer RNA
Microcephaly
Phosphotransferases
Central Nervous System
Mutation
Neurons
RNA Precursors
Motor Neurons
Human Genome
Cell death
Missense Mutation
Genomics
Paralysis
Introns
Muscle
Brain
Cell Death
Genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Karaca, E., Weitzer, S., Pehlivan, D., Shiraishi, H., Gogakos, T., Hanada, T., ... Lupski, J. R. (2014). Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function. Cell, 157(3), 636-650. https://doi.org/10.1016/j.cell.2014.02.058

Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function. / Karaca, Ender; Weitzer, Stefan; Pehlivan, Davut; Shiraishi, Hiroshi; Gogakos, Tasos; Hanada, Toshikatsu; Jhangiani, Shalini N.; Wiszniewski, Wojciech; Withers, Marjorie; Campbell, Ian M.; Erdin, Serkan; Isikay, Sedat; Franco, Luis M.; Gonzaga-Jauregui, Claudia; Gambin, Tomasz; Gelowani, Violet; Hunter, Jill V.; Yesil, Gozde; Koparir, Erkan; Yilmaz, Sarenur; Brown, Miguel; Briskin, Daniel; Hafner, Markus; Morozov, Pavel; Farazi, Thalia A.; Bernreuther, Christian; Glatzel, Markus; Trattnig, Siegfried; Friske, Joachim; Kronnerwetter, Claudia; Bainbridge, Matthew N.; Gezdirici, Alper; Seven, Mehmet; Muzny, Donna M.; Boerwinkle, Eric; Ozen, Mustafa; Clausen, Tim; Tuschl, Thomas; Yuksel, Adnan; Hess, Andreas; Gibbs, Richard A.; Martinez, Javier; Penninger, Josef M.; Lupski, James R.

In: Cell, Vol. 157, No. 3, 24.04.2014, p. 636-650.

Research output: Contribution to journalArticle

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, Clausen, T, Tuschl, T, Yuksel, A, Hess, A, Gibbs, RA, Martinez, J, Penninger, JM & Lupski, JR 2014, 'Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function', Cell, vol. 157, no. 3, pp. 636-650. https://doi.org/10.1016/j.cell.2014.02.058
Karaca E, Weitzer S, Pehlivan D, Shiraishi H, Gogakos T, Hanada T et al. Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function. Cell. 2014 Apr 24;157(3):636-650. https://doi.org/10.1016/j.cell.2014.02.058
Karaca, Ender ; Weitzer, Stefan ; Pehlivan, Davut ; Shiraishi, Hiroshi ; Gogakos, Tasos ; Hanada, Toshikatsu ; Jhangiani, Shalini N. ; Wiszniewski, Wojciech ; Withers, Marjorie ; Campbell, Ian M. ; Erdin, Serkan ; Isikay, Sedat ; Franco, Luis M. ; Gonzaga-Jauregui, Claudia ; Gambin, Tomasz ; Gelowani, Violet ; Hunter, Jill V. ; Yesil, Gozde ; Koparir, Erkan ; Yilmaz, Sarenur ; Brown, Miguel ; Briskin, Daniel ; Hafner, Markus ; Morozov, Pavel ; Farazi, Thalia A. ; Bernreuther, Christian ; Glatzel, Markus ; Trattnig, Siegfried ; Friske, Joachim ; Kronnerwetter, Claudia ; Bainbridge, Matthew N. ; Gezdirici, Alper ; Seven, Mehmet ; Muzny, Donna M. ; Boerwinkle, Eric ; Ozen, Mustafa ; Clausen, Tim ; Tuschl, Thomas ; Yuksel, Adnan ; Hess, Andreas ; Gibbs, Richard A. ; Martinez, Javier ; Penninger, Josef M. ; Lupski, James R. / Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function. In: Cell. 2014 ; Vol. 157, No. 3. pp. 636-650.
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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 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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T1 - Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function

AU - Karaca, Ender

AU - Weitzer, Stefan

AU - Pehlivan, Davut

AU - Shiraishi, Hiroshi

AU - Gogakos, Tasos

AU - Hanada, Toshikatsu

AU - Jhangiani, Shalini N.

AU - Wiszniewski, Wojciech

AU - Withers, Marjorie

AU - Campbell, Ian M.

AU - Erdin, Serkan

AU - Isikay, Sedat

AU - Franco, Luis M.

AU - Gonzaga-Jauregui, Claudia

AU - Gambin, Tomasz

AU - Gelowani, Violet

AU - Hunter, Jill V.

AU - Yesil, Gozde

AU - Koparir, Erkan

AU - Yilmaz, Sarenur

AU - Brown, Miguel

AU - Briskin, Daniel

AU - Hafner, Markus

AU - Morozov, Pavel

AU - Farazi, Thalia A.

AU - Bernreuther, Christian

AU - Glatzel, Markus

AU - Trattnig, Siegfried

AU - Friske, Joachim

AU - Kronnerwetter, Claudia

AU - Bainbridge, Matthew N.

AU - Gezdirici, Alper

AU - Seven, Mehmet

AU - Muzny, Donna M.

AU - Boerwinkle, Eric

AU - Ozen, Mustafa

AU - Clausen, Tim

AU - Tuschl, Thomas

AU - Yuksel, Adnan

AU - Hess, Andreas

AU - Gibbs, Richard A.

AU - Martinez, Javier

AU - Penninger, Josef M.

AU - Lupski, James R.

PY - 2014/4/24

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