Biallelic Mutations in the 3’ Exonuclease TOE1 Cause Pontocerebellar Hypoplasia and Uncover a Role in snRNA Processing

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 ribonucleases with mostly unknown substrate specificity(1). Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration with ambiguous genitalia(2) (MIM%614969). We studied 12 human families with PCH7, uncovering biallelic, loss of function mutations in TOE1 (NC_000001.11), which encodes an unconventional deadenylase(3,4). Toe1-morphant zebrafish displayed mid- and hind-brain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found TOE1 associated with incompletely processed small nuclear (sn)RNAs of the spliceosome, which is responsible for pre-mRNA splicing. 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 immuno-isolated TOE1 complex was sufficient for 3’ end maturation of snRNAs. Our findings reveal the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in processing of snRNA 3’ ends.