Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3′-end RNases with substrate specificity that is mostly unknown1. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia2. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase3,4. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3′ genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3′-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3′-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3′ ends.

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We thank the individuals and their families for their contributions to this study. We thank R. Parker (University of Colorado, Boulder) for U1 constructs and F. Tan for his support with protein modeling. We acknowledge M. Gerstein, S. Mane, A.B. Ekici, S. Uebe and the UCSD IGM Genetics Center for sequencing support and analysis, the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics and the Yale Center for Human Genetics and Genomics. This study was supported by NIH R01GM077243 and R35GM118069 (to J.L.-A.), NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101, the Simons Foundation Autism Research Initiative (SFARI) and the Howard Hughes Medical Institute (to J.G.G.), and NIH HG004659 and NS075449 and California Institute of Regenerative Medicine RB3-05009 (to G.W.Y.). G.W.Y. is an Alfred P. Sloan Research Fellow. E.J.B. was supported by a New Scholar award from the Ellison Medical Foundation and a Hellman Fellowship. R.M.L. is the recipient of an NRSA Postdoctoral Fellowship (NIH F32 GM106706) and is a San Diego IRACDA Fellow (NIH K12 GM06852). A.E.S. is a recipient of an A.P. Gianinni Fellowship and an NIH Pathway to Independence Award (K99HD082337). E.L.V.N. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2172-13). European Research Council Starting Grant 260888 and the Italian Ministry of Health Ricerca Corrente 2015 supported E.M.V. We thank the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur), the University of Washington Center for Mendelian Genomics (UM1HG006493 to M. Bamshad), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M.G.), and the Gregory M. Kiez and Mehmet Kutman Foundation (to M.G.). W.B.D. was supported by NIH R01NS050375.

Author information

Author notes

    • Rea M Lardelli
    • , Ashleigh E Schaffer
    •  & Veerle R C Eggens

    These authors contributed equally to this work.


  1. University of California San Diego, La Jolla, California, USA.

    • Rea M Lardelli
    • , Ashleigh E Schaffer
    • , Tim L Shaw
    • , Eric J Bennett
    • , Jens Lykke-Andersen
    •  & Joseph G Gleeson
  2. Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.

    • Ashleigh E Schaffer
    • , Zinayida Schlachetzki
    • , Basak Rosti
    • , Naiara Akizu
    • , Eric Scott
    • , Jennifer L Silhavy
    • , Laura Dean Heckman
    • , Rasim Ozgur Rosti
    • , Esra Dikoglu
    • , Anne Gregor
    • , Alicia Guemez-Gamboa
    • , Damir Musaev
    • , Rohit Mande
    • , Ari Widjaja
    • , Isaac Marin-Valencia
    •  & Joseph G Gleeson
  3. Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.

    • Ashleigh E Schaffer
    • , Shashank Sathe
    • , Eric L Van Nostrand
    • , Sebastian Markmiller
    •  & Gene W Yeo
  4. Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.

    • Veerle R C Eggens
    •  & Frank Baas
  5. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.

    • Maha S Zaki
  6. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.

    • Stephanie Grainger
    •  & David Traver
  7. Department of Paediatric Medicine, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

    • Justin H Davies
  8. Pediatric Neurology and Metabolic Diseases, Universitair Ziekenhuis Brussels, Vrije Universiteit Brussel, Brussels, Belgium.

    • Linda de Meirleir
  9. Medical Genetics Department, Koc University School of Medicine, Istanbul, Turkey.

    • Hulya Kayserili
  10. Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul Turkey.

    • Umut Altunoglu
  11. Department of Clinical Genetics, The Canberra Hospital, Woden, Australian Capital Territory, Australia.

    • Mary Louise Freckmann
  12. Australian Capital Territory Genetic Service, The Canberra Hospital, Canberra City, Australian Capital Territory, Australia.

    • Linda Warwick
  13. Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • David Chitayat
  14. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

    • David Chitayat
  15. Division of Neuroradiology, Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Susan Blaser
  16. Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul, Turkey.

    • Ahmet Okay Çağlayan
  17. Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Ahmet Okay Çağlayan
    •  & Murat Gunel
  18. Department of Genetics, Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Kaya Bilguvar
  19. Division of Pediatric Neurology, Department of Pediatrics, Erciyes University School of Medicine, Kayseri, Turkey.

    • Huseyin Per
  20. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

    • Christina Fagerberg
  21. Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.

    • Henrik T Christesen
    •  & Maria Kibaek
  22. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.

    • Kimberly A Aldinger
    •  & William B Dobyns
  23. Department of Pediatrics, Clinical Genetics and Metabolism, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.

    • David Manchester
  24. Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

    • Naomichi Matsumoto
    •  & Hirotomo Saitsu
  25. Department of Pediatrics, Gunma University School of Medicine, Showa-machi, Maebashi City, Japan.

    • Kazuhiro Muramatsu
  26. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

    • Hirotomo Saitsu
  27. Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

    • Masaaki Shiina
    •  & Kazuhiro Ogata
  28. Southampton University Hospitals Trust, Southampton, UK.

    • Nicola Foulds
  29. UCSD Cardiology, University of California San Diego, La Jolla, California, USA.

    • Neil C Chi
  30. Clinical Genetics Unit, Department of Women, Mother and Neonates, “Vittore Buzzi” Children's Hospital, Istituti Clinici di Perfezionamento, Milan, Italy.

    • Luigina Spaccini
  31. Child Neurology Unit, Department of Pediatrics, “Vittore Buzzi” Children Hospital, Istituti Clinici di Perfezionamento, Milan, Italy.

    • Stefania Maria Bova
  32. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Stacey B Gabriel
  33. Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.

    • Enza Maria Valente
  34. Pediatric Neurology, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

    • Marie-Cecile Nassogne
  35. Department of Physiology, National University of Singapore and Molecular Engineering Laboratory, A*STAR, Singapore.

    • Gene W Yeo


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A.E.S., S.M., N.A., A.G.-G., L.D.H. and A.G. performed fibroblast, iPSC, NPC and knockout mouse experiments. R.M.L. generated stable cell lines and performed all snRNA/P experiments. V.R.C.E., N.A., E.S., D. Musaev, R.M., A.W., A.E.S., J.L.S., E.D., R.O.R. and H.T.C. analyzed clinical and exome results. S.G., A.E.S., Z.S., B.R., A.G.-G., I.M.-V. and L.D.H. generated zebrafish data, and N.C.C. and D.T. provided resources for zebrafish experimentation. M.S.Z., N.F., W.B.D., L.S., S.M.B., E.M.V., J.H.D., L.d.M., H.K., U.A., M.L.F., L.W., D.C., S.B., C.F., M.K., K.A.A., D. Manchester, N.M., A.O.Ç., K.B., H.P., M.-C.N., H.S., M.S., K.O. and K.M. conceived of the genetic investigation. S.B.G. and M.G. supported exome sequencing. E.L.V.N., S.S., T.L.S. and G.W.Y. supported RNA sequencing and computational analysis. E.J.B. performed mass spectrometry. R.L.M., A.E.S., J.L.-A. and J.G.G. wrote the manuscript. R.M.L., A.E.S., V.R.C.E., Z.S., N.C.C., D.T., G.W.Y., F.B., J.L.-A. and J.G.G. edited the manuscript. J.L.-A., F.B. and J.G.G. directed the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Frank Baas or Jens Lykke-Andersen or Joseph G Gleeson.

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    Supplementary Figures 1–12 and Supplementary Tables 2 and 4

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  1. 1.

    Supplementary Table 1

    Clinical table of patient features.

  2. 2.

    Supplementary Table 3

    LC–MS/MS spectral counts for proteins identified in immunoprecipitations.

  3. 3.

    Supplementary Table 5

    DNA and RNA primers.

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