Dataset Information

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 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.

SUBMITTER: Lardelli RM

PROVIDER: S-EPMC5325768 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Lardelli Rea M RM Schaffer Ashleigh E AE Eggens Veerle R C VR Zaki Maha S MS Grainger Stephanie S Sathe Shashank S Van Nostrand Eric L EL Schlachetzki Zinayida Z Rosti Basak B Akizu Naiara N Scott Eric E Silhavy Jennifer L JL Heckman Laura Dean LD Rosti Rasim Ozgur RO Dikoglu Esra E Gregor Anne A Guemez-Gamboa Alicia A Musaev Damir D Mande Rohit R Widjaja Ari A Shaw Tim L TL Markmiller Sebastian S Marin-Valencia Isaac I Davies Justin H JH de Meirleir Linda L Kayserili Hulya H Altunoglu Umut U Freckmann Mary Louise ML Warwick Linda L Chitayat David D Blaser Susan S Çağlayan Ahmet Okay AO Bilguvar Kaya K Per Huseyin H Fagerberg Christina C Christesen Henrik T HT Kibaek Maria M Aldinger Kimberly A KA Manchester David D Matsumoto Naomichi N Muramatsu Kazuhiro K Saitsu Hirotomo H Shiina Masaaki M Ogata Kazuhiro K Foulds Nicola N Dobyns William B WB Chi Neil C NC Traver David D Spaccini Luigina L Bova Stefania Maria SM Gabriel Stacey B SB Gunel Murat M Valente Enza Maria EM Nassogne Marie-Cecile MC Bennett Eric J EJ Yeo Gene W GW Baas Frank F Lykke-Andersen Jens J Gleeson Joseph G JG

Nature genetics 20170116 3

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 encode ...[more]

PMID: 28092684

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Project description:BACKGROUND: Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. METHODS: We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. RESULTS: EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. CONCLUSIONS: EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.

Dataset Information

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

Publications

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

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