Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.
Rea M Lardelli,
Ashleigh E Schaffer,
Veerle R C Eggens,
Maha S Zaki,
Stephanie Grainger,
Shashank Sathe,
Eric L Van Nostrand,
Zinayida Schlachetzki,
Basak Rosti,
Naiara Akizu,
Eric Scott,
Jennifer L Silhavy,
Laura Dean Heckman,
Rasim Ozgur Rosti,
Esra Dikoglu,
Anne Gregor,
Alicia Guemez-Gamboa,
Damir Musaev,
Rohit Mande,
Ari Widjaja,
Tim L Shaw,
Sebastian Markmiller,
Isaac Marin-Valencia,
Justin H Davies,
Linda de Meirleir,
Hulya Kayserili,
Umut Altunoglu,
Mary Louise Freckmann,
Linda Warwick,
David Chitayat,
Susan Blaser,
Ahmet Okay Çağlayan,
Kaya Bilguvar,
Huseyin Per,
Christina Fagerberg,
Henrik T Christesen,
Maria Kibaek,
Kimberly A Aldinger,
David Manchester,
Naomichi Matsumoto,
Kazuhiro Muramatsu,
Hirotomo Saitsu,
Masaaki Shiina,
Kazuhiro Ogata,
Nicola Foulds,
William B Dobyns,
Neil C Chi,
David Traver,
Luigina Spaccini,
Stefania Maria Bova,
Stacey B Gabriel,
Murat Gunel,
Enza Maria Valente,
Marie-Cecile Nassogne,
Eric J Bennett,
Gene W Yeo,
Frank Baas,
Jens Lykke-Andersen,
Joseph G Gleeson
Nature genetics
· 2017
· Vol. 49
(3)
· pp. 457-464
Abstract
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<sup>2+</sup>-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.
Publication Types
["Journal Article"]
Keywords
MeSH Terms
["Alleles", "Animals", "Cerebellar Diseases", "Exonucleases", "Female", "Humans", "Male", "Mice", "Mutation", "Neurodegenerative Diseases", "Nuclear Proteins", "RNA, Messenger", "RNA, Small Nuclear", "Spliceosomes", "Zebrafish"]
Funding
R01 HG004659
NHGRI NIH HHS
(United States)
R35 GM118069
NIGMS NIH HHS
(United States)
P30 NS047101
NINDS NIH HHS
(United States)
T32 GM007240
NIGMS NIH HHS
(United States)
K12 GM068524
NIGMS NIH HHS
(United States)
R01 NS075449
NINDS NIH HHS
(United States)
UM1 HG008900
NHGRI NIH HHS
(United States)
260888
European Research Council
(International)
R01 GM077243
NIGMS NIH HHS
(United States)
F32 GM106706
NIGMS NIH HHS
(United States)
R01 NS048453
NINDS NIH HHS
(United States)
U54 HG006504
NHGRI NIH HHS
(United States)
R00 HD082337
NICHD NIH HHS
(United States)
R01 NS098004
NINDS NIH HHS
(United States)
UM1 HG006493
NHGRI NIH HHS
(United States)
R01 NS058721
NINDS NIH HHS
(United States)
U54 HG003067
NHGRI NIH HHS
(United States)
R01 NS050375
NINDS NIH HHS
(United States)
R01 NS041537
NINDS NIH HHS
(United States)
K99 HD082337
NICHD NIH HHS
(United States)
R01 NS052455
NINDS NIH HHS
(United States)
P01 HD070494
NICHD NIH HHS
(United States)
Linked Datasets (1)
Biallelic mutations in the 3â exonuclease TOE1 cause Pontocerebellar Hypoplasia Type 7 and result in snRNA processing defects
Homo sapiens154 data files
| File | Type | Size |
|---|---|---|
| Sample100_Expt3_input-U6-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 911.4 KB |
| Sample101_Expt3_input-U6-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 860.2 KB |
| Sample102_Expt3_input-U6-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 2.0 MB |
| Sample103_Expt3_elu-U6-DEaddback.fastq.gz | RIP-Seq | 880.6 KB |
| Sample104_Expt4_input-U6-FLAGonly-siLuc.fastq.gz | RNA-Seq | 1.1 MB |
| Sample105_Expt4_input-U6-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 1003.5 KB |
| Sample106_Expt4_input-U6-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 1.1 MB |
| Sample107_Expt4_input-U6-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 993.3 KB |
| Sample108_Expt4_elu-U6-Wtaddback.fastq.gz | RIP-Seq | 2.2 MB |
| Sample109_Expt4_elu-U6-DEaddback.fastq.gz | RIP-Seq | 256.0 KB |
| Sample10_Expt1_input-U2-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 819.2 KB |
| Sample110_Expt4_FU4-01_siLUCtot_rip41.fastq.gz | RNA-Seq | 1.5 MB |
| Sample111_Expt4_FU4-02_siCaf1ztot_rip41.fastq.gz | RNA-Seq | 1.9 MB |
| Sample112_Expt4_FU4-03_WTtot_rip41.fastq.gz | RNA-Seq | 1.9 MB |
| Sample113_Expt4_FU4-04_DEtot_rip41.fastq.gz | RNA-Seq | 1.6 MB |
| Sample114_Expt4_FU4-05_WTrip_rip41.fastq.gz | RIP-Seq | 4.1 MB |
| Sample115_Expt4_FU4-06_DErip_rip41.fastq.gz | RIP-Seq | 2.8 MB |
| Sample116_Expt6_FU1-Vs-09_siL_tot_42.fastq.gz | RNA-Seq | 1.5 MB |
| Sample117_Expt6_FU1-Vs-10_siC_tot_42.fastq.gz | RNA-Seq | 1.8 MB |
| Sample118_Expt6_FU1-Vs-11_WT_tot_42.fastq.gz | RNA-Seq | 1.6 MB |
| Sample119_Expt6_FU1-Vs-12_DE_tot_42.fastq.gz | RNA-Seq | 1.9 MB |
| Sample11_Expt1_elu-U2-WTaddback.fastq.gz | RIP-Seq | 849.9 KB |
| Sample120_Expt6_FU1-Vs-01_WT_el_42_trizol.fastq.gz | RIP-Seq | 1.4 MB |
| Sample121_Expt6_FU1-Vs-02_WT_el_42_Mg.fastq.gz | RIP-Seq | 1.2 MB |
| Sample122_Expt6_FU1-Vs-03_WT_el_42_EDTA.fastq.gz | RIP-Seq | 471.0 KB |
| Sample123_Expt6_FU1-Vs-04_DE_el_42_trizol.fastq.gz | RIP-Seq | 1.1 MB |
| Sample124_Expt6_FU1-Vs-05_DE_el__42_Mg.fastq.gz | RIP-Seq | 1.2 MB |
| Sample125_Expt6_FU1-Vs-06_DE_el__42_EDTA.fastq.gz | RIP-Seq | 1.5 MB |
| Sample126_Expt7_FU1-Vs-20_siL_tot_40.fastq.gz | RNA-Seq | 1.3 MB |
| Sample127_Expt7_FU1-Vs-21_siC_tot_40.fastq.gz | RNA-Seq | 1.3 MB |
| Sample128_Expt7_FU1-Vs-22_WT_tot_40.fastq.gz | RNA-Seq | 1.2 MB |
| Sample129_Expt7_FU1-Vs-07_DE_tot_40.fastq.gz | RNA-Seq | 1.2 MB |
| Sample12_Expt1_elu-U2-Deaddback.fastq.gz | RIP-Seq | 870.4 KB |
| Sample130_Expt7_FU1-Vs-13_A103_tot_40.fastq.gz | RNA-Seq | 1.4 MB |
| Sample131_Expt7_FU1-Vs-14_F148_tot_40.fastq.gz | RNA-Seq | 1.3 MB |
| Sample132_Expt7_FU1-Vs-15_V173_tot_40.fastq.gz | RNA-Seq | 1.1 MB |
| Sample133_Expt7_FU1-Vs-16_E220_tot_40.fastq.gz | RNA-Seq | 962.6 KB |
| Sample134_Expt9_FU1V68-01_NPC__ATCC.fastq.gz | RNA-Seq | 757.8 KB |
| Sample135_Expt9_FU1V68-02_NPC_1603A1.fastq.gz | RNA-Seq | 931.8 KB |
| Sample136_Expt9_FU1V68-03_NPC_1603A3.fastq.gz | RNA-Seq | 768.0 KB |
| Sample137_Expt9_FU1V68-04_NPC_1603U3.fastq.gz | RNA-Seq | 890.9 KB |
| Sample138_Expt9_FU1V68-05_NPC_1603U4.fastq.gz | RNA-Seq | 716.8 KB |
| Sample139_Expt9_FU2-01_NPC__ATCC.fastq.gz | RNA-Seq | 942.1 KB |
| Sample13_Expt2_input-U1-FLAGonly-siLuc.fastq.gz | RNA-Seq | 471.0 KB |
| Sample140_Expt9_FU2-02_NPC_1603A1.fastq.gz | RNA-Seq | 788.5 KB |
| Sample141_Expt9_FU2-03_NPC_1603A3.fastq.gz | RNA-Seq | 768.0 KB |
| Sample142_Expt9_FU2-04_NPC_1603U3.fastq.gz | RNA-Seq | 911.4 KB |
| Sample143_Expt9_FU2-05_NPC_1603U4.fastq.gz | RNA-Seq | 655.4 KB |
| Sample144_Expt9_FU5-03_NPC__ATCC.fastq.gz | RNA-Seq | 1.4 MB |
| Sample145_Expt9_FU5-04_NPC_1603A1.fastq.gz | RNA-Seq | 1.2 MB |
| Sample146_Expt9_FU5-05_NPC_1603A3.fastq.gz | RNA-Seq | 1.6 MB |
| Sample147_Expt9_FU5-06_NPC_1603U3.fastq.gz | RNA-Seq | 1.3 MB |
| Sample148_Expt9_FU5-07_NPC_1603U4.fastq.gz | RNA-Seq | 1.4 MB |
| Sample149_Expt4_FU5-08_siLuc_tot_41.fastq.gz | RNA-Seq | 1.8 MB |
| Sample14_Expt2_input-U1-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 399.4 KB |
| Sample150_Expt4_FU5-09_siC_tot_41.fastq.gz | RNA-Seq | 2.4 MB |
| Sample151_Expt4_FU5-10_WT_tot_41.fastq.gz | RNA-Seq | 1.7 MB |
| Sample152_Expt4_FU5-11_DE_tot_41.fastq.gz | RNA-Seq | 1.5 MB |
| Sample153_Expt4_FU5-12_WT_el_41.fastq.gz | RIP-Seq | 522.2 KB |
| Sample154_Expt4_FU5-13_DE_el_41.fastq.gz | RIP-Seq | 573.4 KB |
| Sample15_Expt2_input-U1-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 430.1 KB |
| Sample16_Expt2_input-U1-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 471.0 KB |
| Sample17_Expt2_elu-U1-WTaddback.fastq.gz | RIP-Seq | 286.7 KB |
| Sample18_Expt2_elu-U1-DEaddback.fastq.gz | RIP-Seq | 245.8 KB |
| Sample19_Expt2_input-U2-FLAGonly-siLuc.fastq.gz | RNA-Seq | 276.5 KB |
| Sample1_Expt1_input-U1-FLAGonly-siLuc.fastq.gz | RNA-Seq | 522.2 KB |
| Sample20_Expt2_input-U2-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 235.5 KB |
| Sample21_Expt2_input-U2-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 266.2 KB |
| Sample22_Expt2_input-U2-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 276.5 KB |
| Sample23_Expt2_elu-U2-WTaddback.fastq.gz | RIP-Seq | 266.2 KB |
| Sample24_Expt2_elu-U2-DEaddback.fastq.gz | RIP-Seq | 286.7 KB |
| Sample25_Expt2_input-U4-FLAGonly-siLuc.fastq.gz | RNA-Seq | 563.2 KB |
| Sample26_Expt2_input-U4-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 532.5 KB |
| Sample27_Expt2_input-U4-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 460.8 KB |
| Sample28_Expt2_input-U4-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 440.3 KB |
| Sample29_Expt2_elu-U4-WTaddback.fastq.gz | RIP-Seq | 553.0 KB |
| Sample2_Expt1_input-U1-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 604.2 KB |
| Sample30_Expt2_elu-U4-DEaddback.fastq.gz | RIP-Seq | 532.5 KB |
| Sample31_Expt2_input-U5-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 399.4 KB |
| Sample32_Expt2_input-U5-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 409.6 KB |
| Sample33_Expt2_elu-U5-WTaddback.fastq.gz | RIP-Seq | 419.8 KB |
| Sample34_Expt2_elu-U5-DEaddback.fastq.gz | RIP-Seq | 378.9 KB |
| Sample35_Expt2_input-U6-FLAGonly-siLuc.fastq.gz | RNA-Seq | 256.0 KB |
| Sample36_Expt2_input-U6-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 256.0 KB |
| Sample37_Expt2_input-U6-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 286.7 KB |
| Sample38_Expt2_input-U6-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 286.7 KB |
| Sample39_Expt2_elu-U6-Wtaddback.fastq.gz | RIP-Seq | 327.7 KB |
| Sample3_Expt1_input-U1-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 573.4 KB |
| Sample40_Expt2_elu-U6-DEaddback.fastq.gz | RIP-Seq | 348.2 KB |
| Sample41_Expt3_input-U1-FLAGonly-siLuc.fastq.gz | RNA-Seq | 2.3 MB |
| Sample42_Expt3_input-U1-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 2.7 MB |
| Sample43_Expt3_input-U1-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 3.6 MB |
| Sample44_Expt3_input-U1-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 2.5 MB |
| Sample45_Expt3_elu-U1-WTaddback.fastq.gz | RIP-Seq | 3.1 MB |
| Sample46_Expt3_elu-U1-Deaddback.fastq.gz | RIP-Seq | 3.6 MB |
| Sample47_Expt3_input-U2-FLAGonly-siLuc.fastq.gz | RNA-Seq | 3.8 MB |
| Sample48_Expt3_input-U2-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 1.6 MB |
| Sample49_Expt3_input-U2-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 2.1 MB |
| Sample4_Expt1_input-U1-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 573.4 KB |
| Sample50_Expt3_input-U2-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 1.4 MB |
| Sample51_Expt3_elu-U2-WTaddback.fastq.gz | RIP-Seq | 2.4 MB |
| Sample52_Expt3_elu-U2-DEaddback.fastq.gz | RIP-Seq | 1.7 MB |
| Sample53_Expt3_input-U4-FLAGonly-siLuc.fastq.gz | RNA-Seq | 4.4 MB |
| Sample54_Expt3_input-U4-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 3.7 MB |
| Sample55_Expt3_input-U4-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 4.6 MB |
| Sample56_Expt3_input-U4-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 2.9 MB |
| Sample57_Expt3_elu-U4-WTaddback.fastq.gz | RIP-Seq | 3.9 MB |
| Sample58_Expt3_elu-U4-DEaddback.fastq.gz | RIP-Seq | 3.8 MB |
| Sample59_Expt3_input-U5-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 4.0 MB |
| Sample5_Expt1_elu-U1-WTaddback.fastq.gz | RIP-Seq | 542.7 KB |
| Sample60_Expt3_input-U5-DEaddback-siCaf1z.fastq.gz | RNA-Seq | 2.7 MB |
| Sample61_Expt3_elu-U5-WTaddback.fastq.gz | RIP-Seq | 2.5 MB |
| Sample62_Expt3_elu-U5-DEaddback.fastq.gz | RIP-Seq | 2.2 MB |
| Sample63_Expt8_PATFIB_U1_ATCC.fastq.gz | RNA-Seq | 8.7 MB |
| Sample64_Expt8_PATFIB_U1_1603A.fastq.gz | RNA-Seq | 8.7 MB |
| Sample65_Expt8_PATFIB_U1_1603U.fastq.gz | RNA-Seq | 5.3 MB |
| Sample66_Expt8_PATFIB_U1_4127A.fastq.gz | RNA-Seq | 8.1 MB |
| Sample67_Expt8_PATFIB_U1_4128A.fastq.gz | RNA-Seq | 9.1 MB |
| Sample68_Expt8_PATFIB_U1_4128U.fastq.gz | RNA-Seq | 11.8 MB |
| Sample69_Expt4_input-U5-FLAGonly-siLuc.fastq.gz | RIP-Seq | 2.0 MB |
| Sample6_Expt1_elu-U1-DEaddback.fastq.gz | RIP-Seq | 716.8 KB |
| Sample70_Expt4_input-U5-FLAGonly-Caf1z.fastq.gz | RIP-Seq | 1.8 MB |
| Sample71_Expt5_FU1-Vs-01_V173_rip.fastq.gz | RIP-Seq | 1.2 MB |
| Sample72_Expt5_FU1-Vs-02_E220_rip.fastq.gz | RIP-Seq | 1.2 MB |
| Sample73_Expt5_FU1-Vs-03_wt_rip.fastq.gz | RIP-Seq | 819.2 KB |
| Sample74_Expt5_FU1-Vs-04_de_rip.fastq.gz | RIP-Seq | 1.8 MB |
| Sample75_Expt5_FU1-Vs-05_a103_rip.fastq.gz | RIP-Seq | 1.8 MB |
| Sample76_Expt5_FU1-Vs-06_f148_rip.fastq.gz | RIP-Seq | 1.1 MB |
| Sample77_Expt5_FU1-Vs-12_siL_tot.fastq.gz | RNA-Seq | 1.3 MB |
| Sample78_Expt5_FU1-Vs-13_siC_tot.fastq.gz | RNA-Seq | 1.6 MB |
| Sample79_Expt5_FU1-Vs-14_wt_tot.fastq.gz | RNA-Seq | 1.7 MB |
| Sample7_Expt1_input-U2-FLAGonly-siLuc.fastq.gz | RNA-Seq | 747.5 KB |
| Sample80_Expt5_FU1-Vs-15_de_tot.fastq.gz | RNA-Seq | 2.2 MB |
| Sample81_Expt5_FU1-Vs-16_a103_tot.fastq.gz | RNA-Seq | 1.5 MB |
| Sample82_Expt5_FU1-Vs-17_f148_tot.fastq.gz | RNA-Seq | 1.7 MB |
| Sample83_Expt5_FU1-Vs-18_v173_tot.fastq.gz | RNA-Seq | 1.8 MB |
| Sample84_Expt5_FU1-Vs-19_e220_tot.fastq.gz | RNA-Seq | 1.5 MB |
| Sample85_Expt8_PATFIB_U2_ATCC.fastq.gz | RNA-Seq | 901.1 KB |
| Sample86_Expt8_PATFIB_U2_1603A.fastq.gz | RNA-Seq | 686.1 KB |
| Sample87_Expt8_PATFIB_U2_1603U.fastq.gz | RNA-Seq | 778.2 KB |
| Sample88_Expt8_PATFIB_U2_4127A.fastq.gz | RNA-Seq | 1.1 MB |
| Sample89_Expt8_PATFIB_U2_4128A.fastq.gz | RNA-Seq | 727.0 KB |
| Sample8_Expt1_input-U2-FLAGonly-siCaf1z.fastq.gz | RNA-Seq | 716.8 KB |
| Sample90_Expt8_PATFIB_U2_4128U.fastq.gz | RNA-Seq | 1013.8 KB |
| Sample91_Expt8_PATFIB_U5_ATCC.fastq.gz | RNA-Seq | 1.7 MB |
| Sample92_Expt8_PATFIB_U5_1603A.fastq.gz | RNA-Seq | 614.4 KB |
| Sample93_Expt8_PATFIB_U5_1603U.fastq.gz | RNA-Seq | 962.6 KB |
| Sample94_Expt8_PATFIB_U5_4127A.fastq.gz | RNA-Seq | 921.6 KB |
| Sample95_Expt8_PATFIB_U5_4128A.fastq.gz | RNA-Seq | 1.3 MB |
| Sample96_Expt8_PATFIB_U5_4128U.fastq.gz | RNA-Seq | 911.4 KB |
| Sample97_Expt2_FU5-09_siLuc_totalrip35.fastq.gz | RNA-Seq | 2.8 MB |
| Sample98_Expt2_FU5-10_siCaf_totalrip35.fastq.gz | RNA-Seq | 2.7 MB |
| Sample99_Expt3_input-U6-FLAGonly-siLuc.fastq.gz | RNA-Seq | 890.9 KB |
| Sample9_Expt1_input-U2-WTaddback-siCaf1z.fastq.gz | RNA-Seq | 706.6 KB |
Analysis Pipelines (1)
GSE71536 Data Processing
4 steps
geo_data_processing
GSE71536