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

• Published in: Cerebellum (London, England) Vol. 18; no. 3; pp. 422 - 432
• Main Authors: Zanni, Ginevra, De Magistris, P., Nardella, M., Bellacchio, E., Barresi, S., Sferra, A., Ciolfi, A., Motta, M., Lue, H., Moreno-Andres, D., Tartaglia, M., Bertini, E., Antonin, Wolfram
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2019; Springer Nature B.V
• Subjects: Ataxia; Atrophy; Biomedical and Life Sciences; Biomedicine; Cerebellar Ataxia - genetics; Cerebellum; Cytoplasm; Humans; Kidney diseases; Male; Mutation, Missense; Nephrotic syndrome; Neurobiology; Neurology; Neurosciences; Nuclear Pore Complex Proteins - genetics; Nucleoporins; Original Paper; Pedigree; Proteins; Siblings; Young Adult; Whole-exome sequencing (WES); Nuclear pore complex (NPC); Steroid-resistant nephrotic syndrome (SRNS); Non-progressive congenital ataxia (CA); Nucleoporin 93 (NUP93)
• ISSN: 1473-4222; 1473-4230
• DOI: 10.1007/s12311-019-1010-5

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.