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

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.

SUBMITTER: Karaca E

PROVIDER: S-EPMC4146440 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Karaca Ender E Weitzer Stefan S Pehlivan Davut D Shiraishi Hiroshi H Gogakos Tasos T Hanada Toshikatsu T Jhangiani Shalini N SN Wiszniewski Wojciech W Withers Marjorie M Campbell Ian M IM Erdin Serkan S Isikay Sedat S Franco Luis M LM Gonzaga-Jauregui Claudia C Gambin Tomasz T Gelowani Violet V Hunter Jill V JV Yesil Gozde G Koparir Erkan E Yilmaz Sarenur S Brown Miguel M Briskin Daniel D Hafner Markus M Morozov Pavel P Farazi Thalia A TA Bernreuther Christian C Glatzel Markus M Trattnig Siegfried S Friske Joachim J Kronnerwetter Claudia C Bainbridge Matthew N MN Gezdirici Alper A Seven Mehmet M Muzny Donna M DM Boerwinkle Eric E Ozen Mustafa M Clausen Tim T Tuschl Thomas T Yuksel Adnan A Hess Andreas A Gibbs Richard A RA Martinez Javier J Penninger Josef M JM Lupski James R JR

Cell 20140401 3

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 sever ...[more]

PMID: 24766809

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Project description:Purpose of reviewPeripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV.Recent findingsProgress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Dataset Information

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

Publications

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

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