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

TitleBiallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.
Publication TypeJournal Article
Year of Publication2017
AuthorsLardelli, RM, Schaffer, AE, Eggens, VRC, Zaki, MS, Grainger, S, Sathe, S, Van Nostrand, EL, Schlachetzki, Z, Rosti, B, Akizu, N, Scott, E, Silhavy, JL, Heckman, LDean, Rosti, ROzgur, Dikoglu, E, Gregor, A, Guemez-Gamboa, A, Musaev, D, Mande, R, Widjaja, A, Shaw, TL, Markmiller, S, Marin-Valencia, I, Davies, JH, de Meirleir, L, Kayserili, H, Altunoglu, U, Freckmann, MLouise, Warwick, L, Chitayat, D, Blaser, S, Çağlayan, AOkay, Bilguvar, K, Per, H, Fagerberg, C, Christesen, HT, Kibaek, M, Aldinger, KA, Manchester, D, Matsumoto, N, Muramatsu, K, Saitsu, H, Shiina, M, Ogata, K, Foulds, N, Dobyns, WB, Chi, NC, Traver, D, Spaccini, L, Bova, SMaria, Gabriel, SB, Günel, M, Valente, EMaria, Nassogne, M-C, Bennett, EJ, Yeo, GW, Baas, F, Lykke-Andersen, J, Gleeson, JG
JournalNat Genet
Volume49
Issue3
Pagination457-464
Date Published2017 Mar
ISSN1546-1718
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.

DOI10.1038/ng.3762
Alternate JournalNat. Genet.
PubMed ID28092684
PubMed Central IDPMC5325768
Grant ListUM1 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
R01 NS098004 / NS / NINDS 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