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

Journal article


Publication Details

Author(s): 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
Journal: Cell
Publisher: Elsevier (Cell Press)
Publication year: 2014
Volume: 157
Journal issue: 3
Pages range: 636-50
ISSN: 0092-8674


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.



FAU Authors / FAU Editors

Heß, Andreas Prof. Dr.
Lehrstuhl für Pharmakologie und Toxikologie


External institutions with authors

Bezmialem University / Bezmiâlem Vakıf Üniversitesi
Gaziantep Childrens Hospital
Houston Texas Medical Center
Istanbul Medeniyet University / İstanbul Medeniyet Üniversitesi
Istanbul University / İstanbul Üniversitesi
Massachusetts General Hospital
Medizinische Universität Wien
Österreichische Akademie der Wissenschaften
Rockefeller University
Universitätsklinikum Hamburg-Eppendorf (UKE)


How to cite

APA:
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), 636-50. https://dx.doi.org/10.1016/j.cell.2014.02.058

MLA:
Karaca, Ender, et al. "Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function." Cell 157.3 (2014): 636-50.

BibTeX: 

Last updated on 2018-06-10 at 02:51