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tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Abstract

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

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Figure 1: MRI of the brain of subject 2-2 of family Am1a (arrow in Fig. 2b) at 2 months age.
Figure 2: Genetic mapping of the PCH2 locus.
Figure 3: Model of human tRNA-splicing endonuclease (adapted from refs. 18 and 19).
Figure 4: TSEN54 expression in human fetal brain.

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References

  1. Patel, M.S., Becker, L.E., Toi, A., Armstrong, D.L. & Chitayat, D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am. J. Med. Genet. A. 140, 594–603 (2006).

    Article  PubMed  Google Scholar 

  2. Goutieres, F., Aicardi, J. & Farkas, E. Anterior horn cell disease associated with pontocerebellar hypoplasia in infants. J. Neurol. Neurosurg. Psychiatry 40, 370–378 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Barth, P.G. et al. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. Neurology 45, 311–317 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Albrecht, S., Schneider, M.C., Belmont, J. & Armstrong, D.L. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol. 85, 394–399 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Rajab, A. et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11–21. Neurology 60, 1664–1667 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Barth, P.G. et al. Pontocerebellar hypoplasia type 2: a neuropathological update. Acta Neuropathol. 114, 373–386 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Edvardson, S. et al. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am. J. Hum. Genet. 81, 857–862 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Paushkin, S.V., Patel, M., Furia, B.S., Peltz, S.W. & Trotta, C.R. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3′ end formation. Cell 117, 311–321 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. van der Knaap, M.S. et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann. Neurol. 51, 264–270 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Scheper, G.C., van der Knaap, M.S. & Proud, C.G. Translation matters: protein synthesis defects in inherited disease. Nat. Rev. Genet. 8, 711–723 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Strauch, K. et al. Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization. Am. J. Hum. Genet. 66, 1945–1957 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Thiele, H. & Nurnberg, P. HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21, 1730–1732 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Ruschendorf, F. & Nurnberg, P. ALOHOMORA: a tool for linkage analysis using 10K SNP array data. Bioinformatics 21, 2123–2125 (2005).

    Article  PubMed  Google Scholar 

  15. Sztriha, L. & Johansen, J.G. Spectrum of malformations of the hindbrain (cerebellum, pons, and medulla) in a cohort of children with high rate of parental consanguinity. Am. J. Med. Genet. A. 135, 134–141 (2005).

    Article  PubMed  Google Scholar 

  16. Barth, P.G. Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev. 15, 411–422 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Muntoni, F. et al. Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar hypoplasia type 1. Neuropediatrics 30, 243–248 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Hopper, A.K. & Phizicky, E.M. tRNA transfers to the limelight. Genes Dev. 17, 162–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Trotta, C.R., Paushkin, S.V., Patel, M., Li, H. & Peltz, S.W. Cleavage of pre-tRNAs by the splicing endonuclease requires a composite active site. Nature 441, 375–377 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank E. Kirst, R. Niemiec and J. Benit-Deekman for technical assistance, P. de Knijff (Leiden University Medical Center) for the generous supply of control DNA samples and G.J. te Meerman for advice on estimation of mutation age. Financial support was given by Hersenstichting, Heijdeman-Teerhuis fonds, Stichting Irene Kinderziekenhuis, the German Ministry of Education and Research through the National Genome Research Network (01GR0416) and the Anton Meelmeijer Fund (F.B. and R.C.M.H.). We acknowledge the contribution of subject's data and blood samples by A.C.B. Peters, R.H.J.M. Gooskens and O. Van Nieuwenhuizen, Wilhelmina Childrens's Hospital, Utrecht; L. De Meirleir, University Hospital Vrije Universiteit Brussels; R. Korinthenberg, Universitätsklinikum Freiburg; J.H. Begeer, University Medical Center, Groningen; W. Deppe, Klinik Bavaria, Kreischa; G. Blennow, University Hospital Lund; H.G. Brunner and N. Knoers, University Medical Center St. Radboud, Nijmegen; A. Böhring, Westfälische Wilhelms-Universität, Münster; M. Huppke, Elisabeth-Kinderkrankenhaus, Oldenburg; O. Debus, Marien Hospital, Vechta; G. Hageman and R. Baarsma, Medisch Spectrum Twente, The Netherlands; S.A. Lynch, Institute of Human Genetics, New Castle upon Tyne; F. Cowan, Hammersmith Hospital London; M.A.J. de Koning-Tijssen, Academic Medical Center, Amsterdam; and E. Peeters, Juliana Childrens Hospital, The Hague. The authors wish to thank all the families who have voluntarily cooperated in this project.

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Correspondence to Frank Baas.

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Supplementary Figures 1–6, Supplementary Table 1, Supplementary Methods (PDF 446 kb)

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Budde, B., Namavar, Y., Barth, P. et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet 40, 1113–1118 (2008). https://doi.org/10.1038/ng.204

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