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

Rea M. Lardelli, Ashleigh E. Schaffer, Veerle R.C. Eggens, Maha S. Zaki, Stephanie Grainger, Shashank Sathe, Eric L. Van Nostrand, 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 WidjajaTim L. Shaw, Sebastian Markmiller, Isaac Marin-Valencia, Justin H. Davies, Linda De Meirleir, Hulya Kayserili, Umut Altunoglu, Mary Louise Freckmann, Linda Warwick, David Chitayat, Susan Blaser, Ahmet Okay Ça Layan, Kaya Bilguvar, Huseyin Per, Christina Fagerberg, Henrik T. Christesen, Maria Kibaek, Kimberly A. Aldinger, David Manchester, Naomichi Matsumoto, Kazuhiro Muramatsu, Hirotomo Saitsu, Masaaki Shiina, Kazuhiro Ogata, Nicola Foulds, William B. Dobyns, Neil C. Chi, David Traver, Luigina Spaccini, Stefania Maria Bova, Stacey B. Gabriel, Murat Gunel, Enza Maria Valente, Marie Cecile Nassogne, Eric J. Bennett, Gene W. Yeo, Frank Baas, Jens Lykke-Andersen, Joseph G. Gleeson*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

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 Mg 2+ -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.

Original languageEnglish (US)
Pages (from-to)457-464
Number of pages8
JournalNature Genetics
Volume49
Issue number3
DOIs
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing'. Together they form a unique fingerprint.

  • Cite this

    Lardelli, R. M., Schaffer, A. E., Eggens, V. R. C., Zaki, M. S., Grainger, S., Sathe, S., Van Nostrand, E. L., Schlachetzki, Z., Rosti, B., Akizu, N., Scott, E., Silhavy, J. L., Heckman, L. D., Rosti, R. O., Dikoglu, E., Gregor, A., Guemez-Gamboa, A., Musaev, D., Mande, R., ... Gleeson, J. G. (2017). Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nature Genetics, 49(3), 457-464. https://doi.org/10.1038/ng.3762