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

Cell. 2014 Apr 24;157(3):636-50. doi: 10.1016/j.cell.2014.02.058.

Ender Karaca ¹, Stefan Weitzer ², Davut Pehlivan ¹, Hiroshi Shiraishi ², Tasos Gogakos ³, Toshikatsu Hanada ⁴, Shalini N Jhangiani ⁵, Wojciech Wiszniewski ¹, Marjorie Withers ¹, Ian M Campbell ¹, Serkan Erdin ⁶, Sedat Isikay ⁷, Luis M Franco ⁸, Claudia Gonzaga-Jauregui ¹, Tomasz Gambin ¹, Violet Gelowani ¹, Jill V Hunter ⁹, Gozde Yesil ¹⁰, Erkan Koparir ¹¹, Sarenur Yilmaz ¹², Miguel Brown ³, Daniel Briskin ³, Markus Hafner ³, Pavel Morozov ³, Thalia A Farazi ³, Christian Bernreuther ¹³, Markus Glatzel ¹³, Siegfried Trattnig ¹⁴, Joachim Friske ¹⁴, Claudia Kronnerwetter ¹⁴, Matthew N Bainbridge ⁵, Alper Gezdirici ¹¹, Mehmet Seven ¹¹, Donna M Muzny ⁵, Eric Boerwinkle ¹⁵, Mustafa Ozen ¹¹, Baylor Hopkins Center for Mendelian Genomics, Tim Clausen ¹⁶, Thomas Tuschl ³, Adnan Yuksel ¹¹, Andreas Hess ¹⁷, Richard A Gibbs ¹⁸, Javier Martinez ¹⁹, Josef M Penninger ²⁰, James R Lupski ²¹

Affiliations

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2 Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria.
3 Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
4 Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria; Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
5 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
6 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
7 Gaziantep Children's Hospital, Gaziantep 27560, Turkey.
8 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
9 Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
10 Department of Medical Genetics, Bezmialem University, Istanbul 34093, Turkey.
11 Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
12 Istanbul Medeniyet University, Faculty of Medicine, Department of Medical Genetics, Istanbul 34730, Turkey.
13 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
14 Department of Radiology, MR Center of Excellence, Medical University of Vienna, Vienna 1090, Austria.
15 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
16 Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
17 Institute for Experimental Pharmacology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany; Campus Support Facility (CSF), Vienna BioCentre, Vienna 1030, Austria.
18 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
19 Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria. Electronic address: javier.martinez@imba.oeaw.ac.at.
20 Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria. Electronic address: josef.penninger@imba.oeaw.ac.at.
21 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.

PMID: 24766809 DOI: 10.1016/j.cell.2014.02.058

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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