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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 unknown1. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia2. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase3,4. foeí-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 posttranscriptionally 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.
The onset of pontocerebellar neurodegeneration occurs so early that it overlaps with neurodevelopment, and it is thus alternatively referred to as pontocerebellar hypoplasia (PCH)5. PCH7 (MIM 614969) is characterized by neurological deterioration, atrophy or hypoplasia of the pons and cerebellum, muscular hypotonia and breathing abnormalities, in combination with hypogonadism2. This combination of rare conditions suggests a unique syndromic association due to mutation of a single gene, but no locus or causative gene has been identified to date. We recruited 12 families meeting criteria for PCH7, including the index family on the basis of which the condition was defined (Fig. 1a), and we confirmed that the clinical features of these families matched those published for PCH7 (Supplementary Table 1). These features included reduced pons and cerebellum parenchyma (Fig. 1b), ventriculomegaly, thin corpus callosum and variable hypogonadism-ranging from absent gonads to ovarian and uterine remnants or atrophic and undescended testes (Supplementary Fig. 1a,b). All patients and families were enrolled in institutional review board (IRB)-approved protocols at referral institutions and provided consent for study. We performed whole-exome sequencing in the proband and parents from Egyptian families 1275 and 1603. Aligning the genomic variants uncovered a homozygous mutation in TOE1 encoding p.Glu220Lys (NC_000001.11) within a shared haplotype of 500 kb (Fig. 2a and Supplementary Fig. 2a,b), which is indicative of shared ancestry for...