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

  • Author(s): Lardelli, Rea M
  • Schaffer, Ashleigh E
  • Eggens, Veerle RC
  • Zaki, Maha S
  • Grainger, Stephanie
  • Sathe, Shashank
  • Van Nostrand, Eric L
  • Schlachetzki, Zinayida
  • Rosti, Basak
  • Akizu, Naiara
  • Scott, Eric
  • Silhavy, Jennifer L
  • Heckman, Laura Dean
  • Rosti, Rasim Ozgur
  • Dikoglu, Esra
  • Gregor, Anne
  • Guemez-Gamboa, Alicia
  • Musaev, Damir
  • Mande, Rohit
  • Widjaja, Ari
  • Shaw, Tim L
  • Markmiller, Sebastian
  • Marin-Valencia, Isaac
  • Davies, Justin H
  • de Meirleir, Linda
  • Kayserili, Hulya
  • Altunoglu, Umut
  • Freckmann, Mary Louise
  • Warwick, Linda
  • Chitayat, David
  • Blaser, Susan
  • Çağlayan, Ahmet Okay
  • Bilguvar, Kaya
  • Per, Huseyin
  • Fagerberg, Christina
  • Christesen, Henrik T
  • Kibaek, Maria
  • Aldinger, Kimberly A
  • Manchester, David
  • Matsumoto, Naomichi
  • Muramatsu, Kazuhiro
  • Saitsu, Hirotomo
  • Shiina, Masaaki
  • Ogata, Kazuhiro
  • Foulds, Nicola
  • Dobyns, William B
  • Chi, Neil C
  • Traver, David
  • Spaccini, Luigina
  • Bova, Stefania Maria
  • Gabriel, Stacey B
  • Gunel, Murat
  • Valente, Enza Maria
  • Nassogne, Marie-Cecile
  • Bennett, Eric J
  • Yeo, Gene W
  • Baas, Frank
  • Lykke-Andersen, Jens
  • Gleeson, Joseph G
  • et al.

Published Web Location

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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