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.
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RNA Biology (2018)