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

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Lardelli, Rea M Schaffer, Ashleigh E Eggens, Veerle R C Zaki, Maha S Grainger, Stephanie Nassogne, Marie-Cécile [UCL] Gleeson, Joseph G

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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2017
Language Anglais
Journal information "Nature Genetics" - Vol. 49, no. 3, p. 457-464 (2017)
Peer reviewed yes
Publisher Nature Publishing Group ((United States) New York, NY)
issn 1061-4036
e-issn 1546-1718
Publication status Publié
Affiliations UCL - SSS/IONS/NEUR - Clinical Neuroscience
UCL - (SLuc) Service de neurologie pédiatrique
Links
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Bibliographic reference Lardelli, Rea M ; Schaffer, Ashleigh E ; Eggens, Veerle R C ; Zaki, Maha S ; Grainger, Stephanie ; et. al. Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.. In: Nature Genetics, Vol. 49, no. 3, p. 457-464 (2017)
Permanent URL http://hdl.handle.net/2078.1/185588