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Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia

  • Ginevra ZanniEmail author
  • P. De Magistris
  • M. Nardella
  • E. Bellacchio
  • S. Barresi
  • A. Sferra
  • A. Ciolfi
  • M. Motta
  • H. Lue
  • D. Moreno-Andres
  • M. Tartaglia
  • E. Bertini
  • Wolfram AntoninEmail author
Original Paper

Abstract

Nuclear pore complexes (NPCs) are the gateways of the nuclear envelope mediating transport between cytoplasm and nucleus. They form huge complexes of 125 MDa in vertebrates and consist of about 30 different nucleoporins present in multiple copies in each complex. Here, we describe pathogenic variants in the nucleoporin 93 (NUP93) associated with an autosomal recessive form of congenital ataxia. Two rare compound heterozygous variants of NUP93 were identified by whole exome sequencing in two brothers with isolated cerebellar atrophy: one missense variant (p.R537W) results in a protein which does not localize to NPCs and cannot functionally replace the wild type protein, whereas the variant (p.F699L) apparently supports NPC assembly. In addition to its recently described pathological role in steroid-resistant nephrotic syndrome, our work identifies NUP93 as a candidate gene for non-progressive congenital ataxia.

Keywords

Nucleoporin 93 (NUP93) Non-progressive congenital ataxia (CA) Nuclear pore complex (NPC) Steroid-resistant nephrotic syndrome (SRNS) Whole-exome sequencing (WES) 

Notes

Acknowledgements

The authors thank the patients and their family for their participation in this study.

Authors’ Contribution

Conceived and designed the project: GZ and WA. Performed the experiments: PDM, MN, EB, SB, AS, AC, MM, HL, and DMA. Analyzed the data: GZ, WA, EB, and MT. Contributed to the writing of the manuscript: GZ and WA. All authors approved the final version of this manuscript.

Funding

This work was supported by grants from the Italian Ministry of Health (Ricerca Finalizzata NET-2013-02356160 to E.B), Fondazione Bambino Gesù (Vite Coraggiose to M.T), and the German Research Foundation to W.A (AN377/7-1).

Compliance with Ethical Standards

All studies were performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participating subjects.

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

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Fig. S2 (PDF 36 kb)
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Fig. S3 (PDF 218 kb)
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ESM 1 (DOCX 29 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative DisordersBambino Gesù Children’s Hospital, IRCCSRomeItaly
  2. 2.Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen UniversityAachenGermany
  3. 3.Genetics and Rare Diseases Research DivisionBambino Gesù Children’s Hospital, IRCSSRomeItaly

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