2. Academic Validation
  3. Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing

Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing

  • Nat Genet. 2017 Mar;49(3):457-464. doi: 10.1038/ng.3762.
Rea M Lardelli 1,  Ashleigh E Schaffer 1 2 3,  Veerle R C Eggens 4,  Maha S Zaki 5,  Stephanie Grainger 6,  Shashank Sathe 3,  Eric L Van Nostrand 3,  Zinayida Schlachetzki 2,  Basak Rosti 2,  Naiara Akizu 2,  Eric Scott 2,  Jennifer L Silhavy 2,  Laura Dean Heckman 2,  Rasim Ozgur Rosti 2,  Esra Dikoglu 2,  Anne Gregor 2,  Alicia Guemez-Gamboa 2,  Damir Musaev 2,  Rohit Mande 2,  Ari Widjaja 2,  Tim L Shaw 1,  Sebastian Markmiller 3,  Isaac Marin-Valencia 2,  Justin H Davies 7,  Linda de Meirleir 8,  Hulya Kayserili 9,  Umut Altunoglu 10,  Mary Louise Freckmann 11,  Linda Warwick 12,  David Chitayat 13 14,  Susan Blaser 15,  Ahmet Okay Çağlayan 16 17,  Kaya Bilguvar 18,  Huseyin Per 19,  Christina Fagerberg 20,  Henrik T Christesen 21,  Maria Kibaek 21,  Kimberly A Aldinger 22,  David Manchester 23,  Naomichi Matsumoto 24,  Kazuhiro Muramatsu 25,  Hirotomo Saitsu 24 26,  Masaaki Shiina 27,  Kazuhiro Ogata 27,  Nicola Foulds 28,  William B Dobyns 22,  Neil C Chi 29,  David Traver 6,  Luigina Spaccini 30,  Stefania Maria Bova 31,  Stacey B Gabriel 32,  Murat Gunel 17,  Enza Maria Valente 33,  Marie-Cecile Nassogne 34,  Eric J Bennett 1,  Gene W Yeo 3 35,  Frank Baas 4,  Jens Lykke-Andersen 1,  Joseph G Gleeson 1 2
Affiliations

Affiliations

  • 1 University of California San Diego, La Jolla, California, USA.
  • 2 Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
  • 3 Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.
  • 4 Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
  • 5 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
  • 6 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.
  • 7 Department of Paediatric Medicine, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
  • 8 Pediatric Neurology and Metabolic Diseases, Universitair Ziekenhuis Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
  • 9 Medical Genetics Department, Koc University School of Medicine, Istanbul, Turkey.
  • 10 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul Turkey.
  • 11 Department of Clinical Genetics, The Canberra Hospital, Woden, Australian Capital Territory, Australia.
  • 12 Australian Capital Territory Genetic Service, The Canberra Hospital, Canberra City, Australian Capital Territory, Australia.
  • 13 Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 14 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • 15 Division of Neuroradiology, Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 16 Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul, Turkey.
  • 17 Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 18 Department of Genetics, Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 19 Division of Pediatric Neurology, Department of Pediatrics, Erciyes University School of Medicine, Kayseri, Turkey.
  • 20 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • 21 Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
  • 22 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
  • 23 Department of Pediatrics, Clinical Genetics and Metabolism, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
  • 24 Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
  • 25 Department of Pediatrics, Gunma University School of Medicine, Showa-machi, Maebashi City, Japan.
  • 26 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
  • 27 Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 28 Southampton University Hospitals Trust, Southampton, UK.
  • 29 UCSD Cardiology, University of California San Diego, La Jolla, California, USA.
  • 30 Clinical Genetics Unit, Department of Women, Mother and Neonates, "Vittore Buzzi" Children's Hospital, Istituti Clinici di Perfezionamento, Milan, Italy.
  • 31 Child Neurology Unit, Department of Pediatrics, "Vittore Buzzi" Children Hospital, Istituti Clinici di Perfezionamento, Milan, Italy.
  • 32 Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • 33 Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
  • 34 Pediatric Neurology, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
  • 35 Department of Physiology, National University of Singapore and Molecular Engineering Laboratory, A*STAR, Singapore.
PMID: 28092684 DOI: 10.1038/ng.3762
Abstract

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 unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. 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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