Abstract
The target of EGR1 protein 1 (TOE1) is a 3-exonuclease belonging to the Asp-Glu-Asp-Asp deadenylase family that plays a vital role in the maturation of a variety of small nuclear RNAs (snRNAs). Bi-allelic variants in TOE1 have been reported to cause a rare and severe neurodegenerative syndrome, pontocerebellar hypoplasia type 7 (PCH7) (OMIM # 614,969), which is characterized by progressive neurodegeneration, developmental delay, and ambiguous genitalia. Here, we describe the case of a 5-year-6-month-old female Chinese patient who presented with cerebral dysplasia, moderate intellectual disability, developmental delay, and dystonia. Trio whole-exome sequencing revealed two previously unreported heterozygous variants of TOE1 in the patient, including a maternal inherited splicing variant c.237-2A > G and a de novo missense variant c.551G > T, p.Arg184Leu. TA clone sequencing showed trans status of the two variants, indicating the missense variant occurred on the paternal strand in the patient. Clinical features of the patient were mostly concordant with previous reports but brain deformities (enlarged lateral ventricle and deepened cerebellum sulcus without microcephaly and reduced cerebellar volume) were less severe than in typical PCH7 patients. Moreover, the patient had no gonadal malformation, which is common and variable in patients with PCH7. In summary, we report the case of a Chinese patient with atypical PCH7 caused by a novel TOE1 compound variant. Our work suggests that variations in the TOE1 gene can lead to highly variable clinical phenotypes.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of data and materials
Both variants have been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar, accession numbers: SCV001885899 and SCV001895909).
References
Son A, Park JE, Kim VN (2018) PARN and TOE1 constitute a 3’ end maturation module for nuclear non-coding RNAs. Cell Rep 23:888–898
Lardelli RM, Lykke-Andersen J (2020) Competition between maturation and degradation drives human snRNA 3’ end quality control. Genes Dev 34:989–1001
Deng T, Huang Y, Weng K, Lin S, Li Y, Shi G, Chen Y, Huang J, Liu D, Ma W et al (2019) TOE1 acts as a 3’ exonuclease for telomerase RNA and regulates telomere maintenance. Nucleic Acids Res 47:391–405
Sperandio S, Tardito S, Surzycki A, Latterich M, de Belle I (2009) TOE1 interacts with p53 to modulate its transactivation potential. FEBS Lett 583:2165–2170
Jia Y, Mu JC, Ackerman SL (2012) Mutation of a U2 snRNA gene causes global disruption of alternative splicing and neurodegeneration. Cell 148:296–308
Budde BS, Namavar Y, Barth PG, Poll-The BT, Nurnberg G, Becker C, van Ruissen F, Weterman MA, Fluiter K, te Beek ET et al (2008) tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet 40:1113–1118
Lardelli RM, Schaffer AE, Eggens VR, Zaki MS, Grainger S, Sathe S, Van Nostrand EL, Schlachetzki Z, Rosti B, Akizu N et al (2017) Biallelic mutations in the 3’ exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet 49:457–464
Anderson C, Davies JH, Lamont L, Foulds N (2011) Early pontocerebellar hypoplasia with vanishing testes: A new syndrome? Am J Med Genet A 155A:667–672
Yu T, Li J, Li N, Liu R, Ding Y, Chang G, Chen Y, Shen Y, Wang X, Wang J (2016) Obesity and developmental delay in a patient with uniparental disomy of chromosome 2. Int J Obes (Lond) 40:1935–1941
Li, N., Chang, G., Xu, Y., Ding, Y., Li, G., Yu, T., Qing, Y., Li, J., Shen, Y., Wang, J. et al. (2017) Clinical and molecular characterization of patients with fructose 1,6-bisphosphatase deficiency. Int J Mol Sci, 18.
Li J, Shi L, Zhang K, Zhang Y, Hu S, Zhao T, Teng H, Li X, Jiang Y, Ji L et al (2018) VarCards: an integrated genetic and clinical database for coding variants in the human genome. Nucleic Acids Res 46:D1039–D1048
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424
Nuovo, S., Micalizzi, A., Romaniello, R., Arrigoni, F., Ginevrino, M., Casella, A., Serpieri, V., D'Arrigo, S., Briguglio, M., Salerno, G.G. et al. (2021) Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study. J Med Genet.
van Dijk T, Baas F, Barth PG, Poll-The BT (2018) What’s new in pontocerebellar hypoplasia? An update on genes and subtypes. Orphanet J Rare Dis 13:92
Rusch CT, Bolsterli BK, Kottke R, Steinfeld R, Boltshauser E (2020) Pontocerebellar hypoplasia: a pattern recognition approach. Cerebellum 19:569–582
Karaca E, Weitzer S, Pehlivan D, Shiraishi H, Gogakos T, Hanada T, Jhangiani SN, Wiszniewski W, Withers M, Campbell IM et al (2014) Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. Cell 157:636–650
Schaffer AE, Eggens VR, Caglayan AO, Reuter MS, Scott E, Coufal NG, Silhavy JL, Xue Y, Kayserili H, Yasuno K et al (2014) CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell 157:651–663
Breuss MW, Sultan T, James KN, Rosti RO, Scott E, Musaev D, Furia B, Reis A, Sticht H, Al-Owain M et al (2016) Autosomal-recessive mutations in the tRNA splicing endonuclease subunit TSEN15 cause pontocerebellar hypoplasia and progressive microcephaly. Am J Hum Genet 99:228–235
Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, Saada A, Elpeleg O (2007) Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 81:857–862
Agamy O, Ben Zeev B, Lev D, Marcus B, Fine D, Su D, Narkis G, Ofir R, Hoffmann C, Leshinsky-Silver E et al (2010) Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. Am J Hum Genet 87:538–544
Wan J, Yourshaw M, Mamsa H, Rudnik-Schoneborn S, Menezes MP, Hong JE, Leong DW, Senderek J, Salman MS, Chitayat D et al (2012) Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet 44:704–708
Boczonadi V, Muller JS, Pyle A, Munkley J, Dor T, Quartararo J, Ferrero I, Karcagi V, Giunta M, Polvikoski T et al (2014) EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nat Commun 5:4287
Burns DT, Donkervoort S, Muller JS, Knierim E, Bharucha-Goebel D, Faqeih EA, Bell SK, AlFaifi AY, Monies D, Millan F et al (2018) Variants in EXOSC9 disrupt the RNA exosome and result in cerebellar atrophy with spinal motor neuronopathy. Am J Hum Genet 102:858–873
Durmaz B, Wollnik B, Cogulu O, Li Y, Tekgul H, Hazan F, Ozkinay F (2009) Pontocerebellar hypoplasia type III (CLAM): extended phenotype and novel molecular findings. J Neurol 256:416–419
Namavar Y, Barth PG, Kasher PR, van Ruissen F, Brockmann K, Bernert G, Writzl K, Ventura K, Cheng EY, Ferriero DM et al (2011) Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 134:143–156
Acknowledgements
We are deeply grateful to the patient and her family for participating in this study.
Funding
The National Natural Science Foundation of China (Grant No. 82071660), the Program of Shanghai Academic/Technology Research Leader (Grant No. 19XD1422600), the Project of Shuguang Program (Grant No. 18SG14) Science and Technology Research, and the Project of Chongqing Education Commission (Grant No. KJQN201900448) supported this study.
Author information
Authors and Affiliations
Contributions
Hongzhu Chen, Niu Li, and Yufei Xu: writing—original draft, investigation, visualization, conceptualization. Cui Song and Guoqiqng Li: writing—original draft, investigation. Tingting Yu: writing—review and editing. Ruen Yao: resources, writing—review and editing. Jian Wang and Cui Song: funding acquisition Jian Wang and Lin Yang: data curation, conceptualization, supervision. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Ethics approval
All procedures were performed in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000, and the protocol was approved by the Ethics Committee of Shanghai Children’s Medical Center (SCMCIRB- K2020060-1).
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Chen, H., Li, N., Xu, Y. et al. Novel compound heterozygous variant of TOE1 results in a mild type of pontocerebellar hypoplasia type 7: an expansion of the clinical phenotype. Neurogenetics 23, 11–17 (2022). https://doi.org/10.1007/s10048-021-00675-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-021-00675-0