biostudies-literatureUnknown10Kvarnung MVetenskapsrådetHjärnfondenStiftelsen för Strategisk ForskningThe 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 (<i>NFASC</i>). 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 <i>NFASC</i> 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 sFrontiers in genetics896https://www.ebi.ac.uk/biostudies/studies/S-EPMC6769111biostudies-literatureAtaxia in Patients With Bi-Allelic <i>NFASC</i> Mutations and Absence of Full-Length NF186.PMC6769111Syk Lundberg EFalk AKvarnung MNilsson DTaylan FJin ZBirnir BShahsavani MBreeuwsma NAnderlid BMNordgren ANordenskjold MLieden ALaan LLindstrand AMoslem MSchuster JDahl NfalseAtaxia in Patients With Bi-Allelic <i>NFASC</i> Mutations and Absence of Full-Length NF186.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 (<i>NFASC</i>). 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 <i>NFASC</i> 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 s2019-01-01T00:00:00Z20192025-04-21T23:29:38.875Z2019-10-16T07:05:08ZS-EPMC67691113160812310.3389/fgene.2019.00896