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 WidjajaTim 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 Ça Layan, Kaya Bilguvar, Huseyin Per, Christina Fagerberg, Henrik Boye Thybo Christesen, Maria Kibæk, 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

Research output: Contribution to journalLetterResearchpeer-review

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 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.

Original languageEnglish
JournalNature Genetics
Volume49
Issue number3
Pages (from-to)457-464
ISSN1061-4036
DOIs
Publication statusPublished - Mar 2017

Fingerprint

spleen exonuclease
Mutation
Eosinophil Cationic Protein
Disorders of Sex Development
Zebrafish
Mammals

Keywords

  • 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

Cite this

Lardelli, R. M., Schaffer, A. E., Eggens, V. R. C., Zaki, M. S., Grainger, S., Sathe, S., ... Gleeson, J. G. (2017). Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nature Genetics, 49(3), 457-464. https://doi.org/10.1038/ng.3762
Lardelli, Rea M. ; Schaffer, Ashleigh E. ; Eggens, Veerle R C ; Zaki, Maha S. ; Grainger, Stephanie ; Sathe, Shashank ; Van Nostrand, Eric L. ; Schlachetzki, Zinayida ; Rosti, Basak ; Akizu, Naiara ; Scott, Eric ; Silhavy, Jennifer L. ; Heckman, Laura Dean ; Rosti, Rasim Ozgur ; Dikoglu, Esra ; Gregor, Anne ; Guemez-Gamboa, Alicia ; Musaev, Damir ; Mande, Rohit ; Widjaja, Ari ; Shaw, Tim L. ; Markmiller, Sebastian ; Marin-Valencia, Isaac ; Davies, Justin H. ; De Meirleir, Linda ; Kayserili, Hulya ; Altunoglu, Umut ; Freckmann, Mary Louise ; Warwick, Linda ; Chitayat, David ; Blaser, Susan ; Ça Layan, Ahmet Okay ; Bilguvar, Kaya ; Per, Huseyin ; Fagerberg, Christina ; Christesen, Henrik Boye Thybo ; Kibæk, Maria ; Aldinger, Kimberly A. ; Manchester, David ; Matsumoto, Naomichi ; Muramatsu, Kazuhiro ; Saitsu, Hirotomo ; Shiina, Masaaki ; Ogata, Kazuhiro ; Foulds, Nicola ; Dobyns, William B ; Chi, Neil C. ; Traver, David ; Spaccini, Luigina ; Bova, Stefania Maria ; Gabriel, Stacey B ; Gunel, Murat ; Valente, Enza Maria ; Nassogne, Marie Cecile ; Bennett, Eric J. ; Yeo, Gene W. ; Baas, Frank ; Lykke-Andersen, Jens ; Gleeson, Joseph G. / Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. In: Nature Genetics. 2017 ; Vol. 49, No. 3. pp. 457-464.
@article{2da3220168b94396b2e7ed6f220c7bd2,
title = "Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing",
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 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.",
keywords = "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",
author = "Lardelli, {Rea M.} and Schaffer, {Ashleigh E.} and Eggens, {Veerle R C} and Zaki, {Maha S.} and Stephanie Grainger and Shashank Sathe and {Van Nostrand}, {Eric L.} and Zinayida Schlachetzki and Basak Rosti and Naiara Akizu and Eric Scott and Silhavy, {Jennifer L.} and Heckman, {Laura Dean} and Rosti, {Rasim Ozgur} and Esra Dikoglu and Anne Gregor and Alicia Guemez-Gamboa and Damir Musaev and Rohit Mande and Ari Widjaja and Shaw, {Tim L.} and Sebastian Markmiller and Isaac Marin-Valencia and Davies, {Justin H.} and {De Meirleir}, Linda and Hulya Kayserili and Umut Altunoglu and Freckmann, {Mary Louise} and Linda Warwick and David Chitayat and Susan Blaser and {{\cC}a Layan}, {Ahmet Okay} and Kaya Bilguvar and Huseyin Per and Christina Fagerberg and Christesen, {Henrik Boye Thybo} and Maria Kib{\ae}k and Aldinger, {Kimberly A.} and David Manchester and Naomichi Matsumoto and Kazuhiro Muramatsu and Hirotomo Saitsu and Masaaki Shiina and Kazuhiro Ogata and Nicola Foulds and Dobyns, {William B} and Chi, {Neil C.} and David Traver and Luigina Spaccini and Bova, {Stefania Maria} and Gabriel, {Stacey B} and Murat Gunel and Valente, {Enza Maria} and Nassogne, {Marie Cecile} and Bennett, {Eric J.} and Yeo, {Gene W.} and Frank Baas and Jens Lykke-Andersen and Gleeson, {Joseph G}",
year = "2017",
month = "3",
doi = "10.1038/ng.3762",
language = "English",
volume = "49",
pages = "457--464",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",

}

Lardelli, RM, Schaffer, AE, Eggens, VRC, Zaki, MS, Grainger, S, Sathe, S, Van Nostrand, EL, Schlachetzki, Z, Rosti, B, Akizu, N, Scott, E, Silhavy, JL, Heckman, LD, Rosti, RO, Dikoglu, E, Gregor, A, Guemez-Gamboa, A, Musaev, D, Mande, R, Widjaja, A, Shaw, TL, Markmiller, S, Marin-Valencia, I, Davies, JH, De Meirleir, L, Kayserili, H, Altunoglu, U, Freckmann, ML, Warwick, L, Chitayat, D, Blaser, S, Ça Layan, AO, Bilguvar, K, Per, H, Fagerberg, C, Christesen, HBT, Kibæk, M, Aldinger, KA, Manchester, D, Matsumoto, N, Muramatsu, K, Saitsu, H, Shiina, M, Ogata, K, Foulds, N, Dobyns, WB, Chi, NC, Traver, D, Spaccini, L, Bova, SM, Gabriel, SB, Gunel, M, Valente, EM, Nassogne, MC, Bennett, EJ, Yeo, GW, Baas, F, Lykke-Andersen, J & Gleeson, JG 2017, 'Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing', Nature Genetics, vol. 49, no. 3, pp. 457-464. https://doi.org/10.1038/ng.3762

Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. / Lardelli, Rea M.; Schaffer, Ashleigh E.; Eggens, Veerle R C; Zaki, Maha S.; Grainger, Stephanie; Sathe, Shashank; Van Nostrand, Eric L.; Schlachetzki, Zinayida; Rosti, Basak; Akizu, Naiara; Scott, Eric; Silhavy, Jennifer L.; Heckman, Laura Dean; Rosti, Rasim Ozgur; Dikoglu, Esra; Gregor, Anne; Guemez-Gamboa, Alicia; Musaev, Damir; Mande, Rohit; Widjaja, Ari; Shaw, Tim L.; Markmiller, Sebastian; Marin-Valencia, Isaac; Davies, Justin H.; De Meirleir, Linda; Kayserili, Hulya; Altunoglu, Umut; Freckmann, Mary Louise; Warwick, Linda; Chitayat, David; Blaser, Susan; Ça Layan, Ahmet Okay; Bilguvar, Kaya; Per, Huseyin; Fagerberg, Christina; Christesen, Henrik Boye Thybo; Kibæk, Maria; Aldinger, Kimberly A.; Manchester, David; Matsumoto, Naomichi; Muramatsu, Kazuhiro; Saitsu, Hirotomo; Shiina, Masaaki; Ogata, Kazuhiro; Foulds, Nicola; Dobyns, William B; Chi, Neil C.; Traver, David; Spaccini, Luigina; Bova, Stefania Maria; Gabriel, Stacey B; Gunel, Murat; Valente, Enza Maria; Nassogne, Marie Cecile; Bennett, Eric J.; Yeo, Gene W.; Baas, Frank; Lykke-Andersen, Jens; Gleeson, Joseph G.

In: Nature Genetics, Vol. 49, No. 3, 03.2017, p. 457-464.

Research output: Contribution to journalLetterResearchpeer-review

TY - JOUR

T1 - Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing

AU - Lardelli, Rea M.

AU - Schaffer, Ashleigh E.

AU - Eggens, Veerle R C

AU - Zaki, Maha S.

AU - Grainger, Stephanie

AU - Sathe, Shashank

AU - Van Nostrand, Eric L.

AU - Schlachetzki, Zinayida

AU - Rosti, Basak

AU - Akizu, Naiara

AU - Scott, Eric

AU - Silhavy, Jennifer L.

AU - Heckman, Laura Dean

AU - Rosti, Rasim Ozgur

AU - Dikoglu, Esra

AU - Gregor, Anne

AU - Guemez-Gamboa, Alicia

AU - Musaev, Damir

AU - Mande, Rohit

AU - Widjaja, Ari

AU - Shaw, Tim L.

AU - Markmiller, Sebastian

AU - Marin-Valencia, Isaac

AU - Davies, Justin H.

AU - De Meirleir, Linda

AU - Kayserili, Hulya

AU - Altunoglu, Umut

AU - Freckmann, Mary Louise

AU - Warwick, Linda

AU - Chitayat, David

AU - Blaser, Susan

AU - Ça Layan, Ahmet Okay

AU - Bilguvar, Kaya

AU - Per, Huseyin

AU - Fagerberg, Christina

AU - Christesen, Henrik Boye Thybo

AU - Kibæk, Maria

AU - Aldinger, Kimberly A.

AU - Manchester, David

AU - Matsumoto, Naomichi

AU - Muramatsu, Kazuhiro

AU - Saitsu, Hirotomo

AU - Shiina, Masaaki

AU - Ogata, Kazuhiro

AU - Foulds, Nicola

AU - Dobyns, William B

AU - Chi, Neil C.

AU - Traver, David

AU - Spaccini, Luigina

AU - Bova, Stefania Maria

AU - Gabriel, Stacey B

AU - Gunel, Murat

AU - Valente, Enza Maria

AU - Nassogne, Marie Cecile

AU - Bennett, Eric J.

AU - Yeo, Gene W.

AU - Baas, Frank

AU - Lykke-Andersen, Jens

AU - Gleeson, Joseph G

PY - 2017/3

Y1 - 2017/3

N2 - 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.

AB - 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.

KW - Alleles

KW - Animals

KW - Cerebellar Diseases/genetics

KW - Exonucleases/genetics

KW - Female

KW - Humans

KW - Male

KW - Mice

KW - Mutation/genetics

KW - Neurodegenerative Diseases/genetics

KW - Nuclear Proteins/genetics

KW - RNA, Messenger/genetics

KW - RNA, Small Nuclear/genetics

KW - Spliceosomes/genetics

KW - Zebrafish

U2 - 10.1038/ng.3762

DO - 10.1038/ng.3762

M3 - Letter

C2 - 28092684

AN - SCOPUS:85009798889

VL - 49

SP - 457

EP - 464

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -