Biallelic mutations in the 3 ' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing
Date
2017Author
Christesen, Henrik T.
Sathe, Shashank
Van Nostrand, Eric L.
Schlachetzki, Zinayida
Rosti, Basak
Akizu, Naiara
Scott, Eric
Silhavy, Jennifer L.
Heckman, Laura Dean
Dikoglu, Esra
Gregor, Anne
Muramatsu, Kazuhiro
Saitsu, Hirotomo
Shiina, Masaaki
Ogata, Kazuhiro
Foulds, Nicola
Dobyns, William B.
Chi, Neil C.
Traver, David
Spaccini, Luigina
Bova, Stefania Maria
Gabrie, Stacey B.
Gunel, Murat
Valente, Enza Maria
Nassogne, Marie-Cecile
Bennett, Eric J.
Yeo, Gene W.
Baas, Frank
Lykke-Andersen, Jens
Gleeson, Joseph G.
Bilguvar, Kaya
Altunoglu, Umut
Rosti, Rasim Ozgur
Guemez-Gamboa, Alicia
Musaev, Damir
Mande, Rohit
Widjaja, Ari
Shaw, Tim L.
Markmiller, Sebastian
Marin-Valencia, Isaac
Davies, Justin H.
de Meirleir, Linda
Kayserili, Hulya
Freckmann, Mary Louise
Warwick, Linda
Chitayat, David
Blaser, Susan
Caglayan, Ahmet Okay
PER, HÜSEYİN
Fagerberg, Christina
Kibaek, Maria
Aldinger, Kimberly A.
Manchester, David
Matsumoto, Naomichi
Lardelli, Rea M.
Schaffer, Ashleigh E.
Eggens, Veerle R. C.
Zaki, Maha S.
Grainger, Stephanie
Metadata
Show full item recordAbstract
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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