title: Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.
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.
authors.affiliation: University of California San Diego, La Jolla, California, USA.
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authors.initials: RM
authors.lastname: Lardelli
authors.affiliation: University of California San Diego, La Jolla, California, USA.|Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.|Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.
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authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.
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authors.affiliation: Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.
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authors.affiliation: Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.affiliation: Laboratory of Pediatric Brain Disease and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
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authors.identifier: http://orcid.org/0000-0003-3912-5428
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mesh_terms: D000483:Alleles; D000818:Animals; D002526:Cerebellar Diseases / Q000235:genetics*; D005092:Exonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012342:RNA, Small Nuclear / Q000235:genetics*; D017381:Spliceosomes / Q000235:genetics; D015027:Zebrafish
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; D012342:RNA, Small Nuclear; C474027:TOE1 protein, human; D005092:Exonucleases