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

TitleHuman CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.
Publication TypeJournal Article
Year of Publication2014
AuthorsKaraca, 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
Corporate Authors
JournalCell
Volume157
Issue3
Pagination636-50
Date Published2014 Apr 24
ISSN1097-4172
KeywordsAbnormalities, Multiple, Animals, Central Nervous System Diseases, Cerebrum, Child, Preschool, Endoribonucleases, Female, Fibroblasts, Humans, Infant, Male, Mice, Mice, Inbred CBA, Microcephaly, Mutation, Missense, Nuclear Proteins, Peripheral Nervous System Diseases, Phosphotransferases, RNA, Transfer, Transcription Factors
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.

DOI10.1016/j.cell.2014.02.058
Alternate JournalCell
PubMed ID24766809
PubMed Central IDPMC4146440
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
K23 NS078056 / NS / NINDS NIH HHS / United States
K23 AI087821 / AI / NIAID NIH HHS / United States
1K23AI087821-01 / AI / NIAID NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
K23NS078056 / NS / NINDS NIH HHS / United States