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Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

Efthymiou, S; Salpietro, V; Malintan, N; Poncelet, M; Kriouile, Y; Fortuna, S; De Zorzi, R; Payne, K; Henderson, LB; Cortese, A; et al. Efthymiou, S; Salpietro, V; Malintan, N; Poncelet, M; Kriouile, Y; Fortuna, S; De Zorzi, R; Payne, K; Henderson, LB; Cortese, A; Maddirevula, S; Alhashmi, N; Wiethoff, S; Ryten, M; Botia, JA; Provitera, V; Schuelke, M; Vandrovcova, J; SYNAPS Study Group; Walsh, L; Torti, E; Iodice, V; Najafi, M; Karimiani, EG; Maroofian, R; Siquier-Pernet, K; Boddaert, N; De Lonlay, P; Cantagrel, V; Aguennouz, M; El Khorassani, M; Schmidts, M; Alkuraya, FS; Edvardson, S; Nolano, M; Devaux, J; Houlden, H (2019) Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination. Brain, 142 (10). pp. 2948-2964. ISSN 1460-2156 https://doi.org/10.1093/brain/awz248
SGUL Authors: Karimiani, Ehsan Ghayoor

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Abstract

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

Item Type: Article
Additional Information: © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: neurodevelopment, neurofascin, peripheral demyelination, SYNAPS Study Group, 11 Medical And Health Sciences, 17 Psychology And Cognitive Sciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Brain
ISSN: 1460-2156
Language: eng
Dates:
DateEvent
October 2019Published
9 September 2019Published Online
18 June 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
WT093205Wellcome Trusthttp://dx.doi.org/10.13039/100004440
WT104033AIAWellcome Trusthttp://dx.doi.org/10.13039/100004440
MR/S01165X/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/S005021/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0601943Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
DFG CRC1140 KIDGEMDeutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
716344European Research Councilhttp://dx.doi.org/10.13039/501100000781
21532Association Francaise contre les Myopathieshttp://dx.doi.org/10.13039/100007393
31–7635 41/67/1European Social Fundhttp://dx.doi.org/10.13039/501100004895
PubMed ID: 31501903
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111182
Publisher's version: https://doi.org/10.1093/brain/awz248

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