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Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186

Kvarnung, Malin ; Shahsavani, Mansoureh ; Taylan, Fulya ; Moslem, Mohsen ; Breeuwsma, Nicole ; Laan, Loora ; Schuster, Jens ; Jin, Zhe LU ; Nilsson, Daniel LU and Lieden, Agne , et al. (2019) In Frontiers in Genetics 10.
Abstract

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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Frontiers in Genetics
volume
10
article number
896
pages
11 pages
publisher
Frontiers Media S. A.
external identifiers
  • pmid:31608123
  • scopus:85073106551
ISSN
1664-8021
DOI
10.3389/fgene.2019.00896
language
English
LU publication?
no
id
af41358b-b82f-47b6-8fbe-6ff7bcbae3d1
date added to LUP
2021-08-09 15:36:05
date last changed
2024-10-06 01:51:13
@article{af41358b-b82f-47b6-8fbe-6ff7bcbae3d1,
  abstract     = {{<p>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 &gt; 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.</p>}},
  author       = {{Kvarnung, Malin and Shahsavani, Mansoureh and Taylan, Fulya and Moslem, Mohsen and Breeuwsma, Nicole and Laan, Loora and Schuster, Jens and Jin, Zhe and Nilsson, Daniel and Lieden, Agne and Anderlid, Britt-Marie and Nordenskjöld, Magnus and Syk Lundberg, Elisabeth and Birnir, Bryndis and Dahl, Niklas and Nordgren, Ann and Lindstrand, Anna and Falk, Anna}},
  issn         = {{1664-8021}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Genetics}},
  title        = {{Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186}},
  url          = {{https://lup.lub.lu.se/search/files/101034464/Ataxia_in_Patients_With_Bi_Allelic.pdf}},
  doi          = {{10.3389/fgene.2019.00896}},
  volume       = {{10}},
  year         = {{2019}},
}