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Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186
Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden;Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Inst, Biomed, Dept Neurosci, Stockholm, Sweden.
Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
Karolinska Inst, Biomed, Dept Neurosci, Stockholm, Sweden.
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2019 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, article id 896Article in journal (Refereed) Published
Abstract [en]

The etiology of hereditary ataxia syndromes is heterogeneous, and the mechanisms underlying these disorders are often unknown. Here, we utilized exome sequencing in two siblings with progressive ataxia and muscular weakness and identified a novel homozygous splice mutation (c.3020-1G > A) in neurofascin (NFASC). In RNA extracted from fibroblasts, we showed that the mutation resulted in inframe skipping of exon 26, with a deprived expression of the full-length transcript that corresponds to NFASC isoform NF186. To further investigate the disease mechanisms, we reprogrammed fibroblasts from one affected sibling to induced pluripotent stem cells, directed them to neuroepithelial stem cells and finally differentiated to neurons. In early neurogenesis, differentiating cells with selective depletion of the NF186 isoform showed significantly reduced neurite outgrowth as well as fewer emerging neurites. Furthermore, whole-cell patch-clamp recordings of patient-derived neuronal cells revealed a lower threshold for openings, indicating altered Na+ channel kinetics, suggesting a lower threshold for openings as compared to neuronal cells without the NFASC mutation. Taken together, our results suggest that loss of the full-length NFASC isoform NF186 causes perturbed neurogenesis and impaired neuronal biophysical properties resulting in a novel early-onset autosomal recessive ataxia syndrome.

Place, publisher, year, edition, pages
2019. Vol. 10, article id 896
Keywords [en]
neurofascin, neuronal isoform NF186, ataxia, patient-specific induced pluripotent stem cells, neuroepithelial stem cells, neurites
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-395798DOI: 10.3389/fgene.2019.00896ISI: 000487628800001OAI: oai:DiVA.org:uu-395798DiVA, id: diva2:1365629
Funder
Swedish Research Council, 2015-02424Swedish Research Council, 2017-03407Swedish Research Council, 2017-02936Swedish Foundation for Strategic Research , IB13-0074The Swedish Brain FoundationSwedish Society for Medical Research (SSMF)Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-12-09Bibliographically approved
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