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