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

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)

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Publication Type: Journal article

Publication year: 2014

Journal

Publisher: Elsevier (Cell Press)

Book Volume: 157

Pages Range: 636-50

Journal Issue: 3

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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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.

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