Journal
NATURE GENETICS
Volume 49, Issue 3, Pages 457-464Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3762
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Funding
- NIH [R01GM077243, R35GM118069, NIH R0INS041537, R0INS048453, R01NS052455, P01HD070494, P30NS047101, R01NS050375]
- Simons Foundation Autism Research Initiative (SFARI)
- Howard Hughes Medical Institute [NIH HG004659, NS075449]
- California Institute of Regenerative Medicine [RB3-05009]
- Ellison Medical Foundation
- NRSA Postdoctoral Fellowship [NIH F32 GM106706]
- NIH Pathway to Independence Award [K99HD082337]
- European Research Council Starting Grant [260888]
- Italian Ministry of Health Ricerca Corrente
- A.P. Gianinni Fellowship
- Hellman Fellowship
- [NIH K12 GM06852]
- Grants-in-Aid for Scientific Research [24118001, 24118005, 26330331, 16H03293] Funding Source: KAKEN
- European Research Council (ERC) [260888] Funding Source: European Research Council (ERC)
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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 unknowns. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia(2). We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase(3,4). 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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