Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.
Authors | |
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. |
Year of Publication | 2017
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Journal | Nat Genet
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Volume | 49
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Issue | 3
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Pages | 457-464
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Date Published | 2017 Mar
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ISSN | 1546-1718
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DOI | 10.1038/ng.3762
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PubMed ID | 28092684
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PubMed Central ID | PMC5325768
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Links | |
Grant list | UM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 GM077243 / GM / NIGMS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R35 GM118069 / GM / NIGMS NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
F32 GM106706 / GM / NIGMS NIH HHS / United States
R01 NS050375 / NS / NINDS NIH HHS / United States
R01 NS041537 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 HG004659 / HG / NHGRI NIH HHS / United States
K99 HD082337 / HD / NICHD NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 NS058721 / NS / NINDS NIH HHS / United States
R01 NS075449 / NS / NINDS NIH HHS / United States
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