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Ataxia in Patients ...
Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186
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- Kvarnung, Malin (author)
- Karolinska Institutet
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- Shahsavani, Mansoureh (author)
- Karolinska Institutet
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- Taylan, Fulya (author)
- Karolinska Institutet
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- Moslem, Mohsen (author)
- Karolinska Institutet
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- Breeuwsma, Nicole (author)
- Karolinska Inst, Biomed, Dept Neurosci, Stockholm, Sweden
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- Laan, Loora (author)
- Uppsala universitet,Medicinsk genetik och genomik,Science for Life Laboratory, SciLifeLab
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- Schuster, Jens, Assistant Professor, 1972- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik
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- Jin, Zhe (author)
- Uppsala universitet,Birnir: Molekylär fysiologi och neurovetenskap
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- Nilsson, Daniel (author)
- Karolinska Institutet
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- Lieden, Agne (author)
- Karolinska Institutet
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- Anderlid, Britt-Marie (author)
- Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden;Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden
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- Nordenskjold, Magnus (author)
- Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden;Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden
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- Lundberg, Elisabeth Syk (author)
- Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden;Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden
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- Birnir, Bryndis (author)
- Uppsala universitet,Birnir: Molekylär fysiologi och neurovetenskap
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- Dahl, Niklas (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik
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- Nordgren, Ann (author)
- Karolinska Institutet
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- Lindstrand, Anna (author)
- Karolinska Institutet
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- Falk, Anna (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2019-09-24
- 2019
- English.
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In: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 10
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- neurofascin
- neuronal isoform NF186
- ataxia
- patient-specific induced pluripotent stem cells
- neuroepithelial stem cells
- neurites
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Kvarnung, Malin
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Shahsavani, Mans ...
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Taylan, Fulya
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Moslem, Mohsen
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Breeuwsma, Nicol ...
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Laan, Loora
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Schuster, Jens, ...
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Jin, Zhe
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Nilsson, Daniel
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Lieden, Agne
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Anderlid, Britt- ...
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Nordenskjold, Ma ...
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Lundberg, Elisab ...
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Birnir, Bryndis
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Dahl, Niklas
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Nordgren, Ann
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Lindstrand, Anna
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Falk, Anna
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Frontiers in Gen ...
- By the university
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Uppsala University
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Karolinska Institutet