ZFIN ID: ZDB-PUB-170117-3
Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing
Lardelli, R.M., Schaffer, A.E., Eggens, V.R., Zaki, M.S., Grainger, S., Sathe, S., Van Nostrand, E.L., Schlachetzki, Z., Rosti, B., Akizu, N., Scott, E., Silhavy, J.L., Heckman, L.D., Rosti, R.O., Dikoglu, E., Gregor, A., Guemez-Gamboa, A., Musaev, D., Mande, R., Widjaja, A., Shaw, T.L., Markmiller, S., Marin-Valencia, I., Davies, J.H., de Meirleir, L., Kayserili, H., Altunoglu, U., Freckmann, M.L., Warwick, L., Chitayat, D., Blaser, S., Çağlayan, A.O., Bilguvar, K., Per, H., Fagerberg, C., Christesen, H.T., Kibaek, M., Aldinger, K.A., Manchester, D., Matsumoto, N., Muramatsu, K., Saitsu, H., Shiina, M., Ogata, K., Foulds, N., Dobyns, W.B., Chi, N.C., Traver, D., Spaccini, L., Bova, S.M., Gabriel, S.B., Gunel, M., Valente, E.M., Nassogne, M.C., Bennett, E.J., Yeo, G.W., Baas, F., Lykke-Andersen, J., Gleeson, J.G.
Date: 2017
Source: Nature Genetics   49(3): 457-464 (Journal)
Registered Authors: Baas, Frank, Chi, Neil C., Grainger, Stephanie, Lardelli, Rea, Markmiller, Sebastian, Traver, David
Keywords: Medical genetics, Molecular biology, Neurological disorders
MeSH Terms:
  • Alleles
  • Animals
  • Cerebellar Diseases/genetics*
  • Exonucleases/genetics*
  • Female
  • Humans
  • Male
  • Mice
  • Mutation/genetics*
  • Neurodegenerative Diseases/genetics
  • Nuclear Proteins/genetics*
  • RNA, Messenger/genetics
  • RNA, Small Nuclear/genetics*
  • Spliceosomes/genetics
  • Zebrafish
PubMed: 28092684 Full text @ Nat. Genet.
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 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.