Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ender
E
Karaca
Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria.
Stefan
S
Weitzer
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Davut
D
Pehlivan
Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria.
Hiroshi
H
Shiraishi
Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
Tasos
T
Gogakos
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.
Toshikatsu
T
Hanada
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Shalini N
SN
Jhangiani
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Wojciech
W
Wiszniewski
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Marjorie
M
Withers
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ian M
IM
Campbell
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Serkan
S
Erdin
Gaziantep Children's Hospital, Gaziantep 27560, Turkey.
Sedat
S
Isikay
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.
Luis M
LM
Franco
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Claudia
C
Gonzaga-Jauregui
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Tomasz
T
Gambin
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Violet
V
Gelowani
Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
Jill V
JV
Hunter
Department of Medical Genetics, Bezmialem University, Istanbul 34093, Turkey.
Gozde
G
Yesil
Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
Erkan
E
Koparir
Istanbul Medeniyet University, Faculty of Medicine, Department of Medical Genetics, Istanbul 34730, Turkey.
Sarenur
S
Yilmaz
Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
Miguel
M
Brown
Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
Daniel
D
Briskin
Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
Markus
M
Hafner
Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
Pavel
P
Morozov
Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
Thalia A
TA
Farazi
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Christian
C
Bernreuther
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Markus
M
Glatzel
Department of Radiology, MR Center of Excellence, Medical University of Vienna, Vienna 1090, Austria.
Siegfried
S
Trattnig
Department of Radiology, MR Center of Excellence, Medical University of Vienna, Vienna 1090, Austria.
Joachim
J
Friske
Department of Radiology, MR Center of Excellence, Medical University of Vienna, Vienna 1090, Austria.
Claudia
C
Kronnerwetter
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Matthew N
MN
Bainbridge
Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
Alper
A
Gezdirici
Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
Mehmet
M
Seven
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Donna M
DM
Muzny
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.
Eric
E
Boerwinkle
Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
Mustafa
M
Ozen
Institute of Molecular Pathology (IMP), 1030 Vienna, Austria.
Tim
T
Clausen
Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY 10065, USA.
Thomas
T
Tuschl
Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
Adnan
A
Yuksel
Institute for Experimental Pharmacology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany; Campus Support Facility (CSF), Vienna BioCentre, Vienna 1030, Austria.
Andreas
A
Hess
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.
Richard A
RA
Gibbs
Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria. Electronic address: javier.martinez@imba.oeaw.ac.at.
Javier
J
Martinez
Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, 1030 Vienna, Austria. Electronic address: josef.penninger@imba.oeaw.ac.at.
Josef M
JM
Penninger
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.
James R
JR
Lupski
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000818:Animals; D002493:Central Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D054022:Cerebrum / Q000473:pathology; D002675:Child, Preschool; D004722:Endoribonucleases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008831:Microcephaly / Q000235:genetics; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D010770:Phosphotransferases / Q000378:metabolism*; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism*
C118642:Hexim1 protein, mouse; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D012343:RNA, Transfer; C520030:CLP1 protein, human; D010770:Phosphotransferases; D004722:Endoribonucleases; C051012:splicing endonuclease