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; 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

doi:10.1016/j.cell.2014.02.058

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 YilmazMiguel 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 journal › Article › peer-review

163 Scopus citations

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 language	English (US)
Pages (from-to)	636-650
Number of pages	15
Journal	Cell
Volume	157
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2014.02.058
State	Published - Apr 24 2014
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2014.02.058

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Karaca, E., Weitzer, S., Pehlivan, D., Shiraishi, H., Gogakos, T., Hanada, T., Jhangiani, S. N., Wiszniewski, W., Withers, M., Campbell, I. M., Erdin, S., Isikay, S., Franco, L. M., Gonzaga-Jauregui, C., Gambin, T., Gelowani, V., Hunter, J. V., Yesil, G., Koparir, E., ... 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

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

@article{88786c04cb1540b699d63db449ca7c0e,

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

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.",

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

note = "Funding Information: We thank the patients and families who participated in this study. We thank the CSF/PIF MRI imaging facility at the campus Vienna BioCenter. This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 and US National Human Genome Research Institute (NHGRI) grant U54HG006542 to J.R.L. H.S. is supported in part by the fellowship of Astellas Foundation for Research on Metabolic Disorders and The Mochida Memorial Foundation for Medical and Pharmaceutical Research. W.W. is supported by a K23NS078056 grant from the NINDS. M.G. is supported by grants from the DFG (FG885 and GRK 1459). J.M. and S.W. are supported by IMBA. J.M.P. is supported by an Advanced ERC grant and IMBA. L.M.F. is supported by a Career Development Award (1K23AI087821-01) from the NIAID. J.R.L. is a paid consultant for Athena Diagnostics, has stock ownership in 23andMe and Ion Torrent Systems, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the clinical exome sequencing offered in the Medical Genetics Laboratory (MGL; http://www.bcm.edu/geneticlabs/ ). ",

year = "2014",

month = apr,

day = "24",

doi = "10.1016/j.cell.2014.02.058",

language = "English (US)",

volume = "157",

pages = "636--650",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

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TY - JOUR

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.

N1 - Funding Information: We thank the patients and families who participated in this study. We thank the CSF/PIF MRI imaging facility at the campus Vienna BioCenter. This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 and US National Human Genome Research Institute (NHGRI) grant U54HG006542 to J.R.L. H.S. is supported in part by the fellowship of Astellas Foundation for Research on Metabolic Disorders and The Mochida Memorial Foundation for Medical and Pharmaceutical Research. W.W. is supported by a K23NS078056 grant from the NINDS. M.G. is supported by grants from the DFG (FG885 and GRK 1459). J.M. and S.W. are supported by IMBA. J.M.P. is supported by an Advanced ERC grant and IMBA. L.M.F. is supported by a Career Development Award (1K23AI087821-01) from the NIAID. J.R.L. is a paid consultant for Athena Diagnostics, has stock ownership in 23andMe and Ion Torrent Systems, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the clinical exome sequencing offered in the Medical Genetics Laboratory (MGL; http://www.bcm.edu/geneticlabs/ ).

PY - 2014/4/24

Y1 - 2014/4/24

N2 - 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.

AB - 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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JO - Cell

JF - Cell

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ER -

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

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