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. © 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
Original languageEnglish
Pages (from-to)2948-2964
Number of pages17
JournalBrain
Volume142
Issue number10
DOIs
Publication statusPublished - 2019

Fingerprint

Ranvier's Nodes
Demyelinating Diseases
Protein Isoforms
Inborn Genetic Diseases
Mutation
Exome
Cell Aggregation
Brain
Cell Adhesion Molecules
Human Development
Licensure
Peripheral Nerves
Neuroglia
Intellectual Disability
Synapses
Nervous System
Genes
Fluorescent Antibody Technique
Immunoglobulins
Observation

Keywords

  • Neurodevelopment
  • Neurofascin
  • Peripheral demyelination
  • cell adhesion molecule
  • isoprotein
  • neurofascin
  • neurofascin 155
  • unclassified drug
  • adolescent
  • adult
  • Article
  • cell aggregation
  • child
  • clinical article
  • controlled study
  • demyelinating neuropathy
  • demyelination
  • developmental delay
  • embryo
  • female
  • fibronectin type III domain
  • frameshift mutation
  • gene mutation
  • human
  • human cell
  • human tissue
  • immunofluorescence test
  • immunohistochemistry
  • intellectual impairment
  • male
  • mental disease
  • motor dysfunction
  • myelinated nerve
  • preschool child
  • priority journal
  • protein expression
  • school child
  • speech disorder
  • whole exome sequencing
  • whole genome sequencing
  • young adult

Cite this

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination. / SYNAPS Study Group.

In: Brain, Vol. 142, No. 10, 2019, p. 2948-2964.

Research output: Contribution to journalArticle

@article{19c91e41cd2047a48f7e4e03ed1fe5f1,
title = "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination",
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. {\circledC} 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",
keywords = "Neurodevelopment, Neurofascin, Peripheral demyelination, cell adhesion molecule, isoprotein, neurofascin, neurofascin 155, unclassified drug, adolescent, adult, Article, cell aggregation, child, clinical article, controlled study, demyelinating neuropathy, demyelination, developmental delay, embryo, female, fibronectin type III domain, frameshift mutation, gene mutation, human, human cell, human tissue, immunofluorescence test, immunohistochemistry, intellectual impairment, male, mental disease, motor dysfunction, myelinated nerve, preschool child, priority journal, protein expression, school child, speech disorder, whole exome sequencing, whole genome sequencing, young adult",
author = "{SYNAPS Study Group} and S. Efthymiou and V. Salpietro and N. Malintan and M. Poncelet and Y. Kriouile and S. Fortuna and {De Zorzi}, R. and K. Payne and L.B. Henderson and A. Cortese and S. Maddirevula and N. Alhashmi and S. Wiethoff and M. Ryten and J.A. Botia and V. Provitera and M. Schuelke and J. Vandrovcova and L. Walsh and E. Torti and V. Iodice and M. Najafi and E.G. Karimiani and R. Maroofian and K. Siquier-Pernet and N. Boddaert and {De Lonlay}, P. and V. Cantagrel and M. Aguennouz and {El Khorassani}, M. and M. Schmidts and F.S. Alkuraya and S. Edvardson and M. Nolano and J. Devaux and H. Houlden and S. Groppa and B.M. Karashova and W. Nachbauer and S. Boesch and P. Veggiotti and M.D. Ferrari and G. Marseglia and S. Savasta and B. Garavaglia and E. Borgione and S. Portaro and C. Scuderi and C. Minetti and S. Rinaldi",
note = "Cited By :1 Export Date: 14 January 2020 CODEN: BRAIA Correspondence Address: Houlden, H.; Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, United Kingdom; email: h.houlden@ucl.ac.uk Funding details: Wellcome Trust, WT Funding details: Muscular Dystrophy UK, MDUK Funding details: Ataxia UK Funding details: European Social Fund, ESF Funding details: Deutsche Forschungsgemeinschaft, DFG, DFG CRC1140 KIDGEM Funding details: Medical Research Council, MRC, MR/S01165X/1, G0601943, MR/S005021/1 Funding details: Brain Research UK Funding details: National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology Funding details: Multiple System Atrophy Trust, MSAT Funding details: 716344 Funding details: Association Fran{\cc}aise contre les Myopathies, AFM, 21532 Funding details: European Research Council, ERC Funding details: Muscular Dystrophy Association, MDA Funding details: Media Development Authority - Singapore, MDA, HP10CRVL7F Funding details: Ministry of Science,Technology and Research, MoSTR Funding details: College of Environmental Science and Forestry, State University of New York, ESF, 7635 41/67/1 Funding details: Rosetrees Trust Funding text 1: We greatly appreciate the financial support provided by The Wellcome Trust and strategic award (Synaptopathies) Funding text 2: funding (WT093205 MA and WT104033AIA). Grunt funding was provided by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). We also acknowledge the CINECA Awards N. HP10CRVL7F, 2017, for the availability of high-performance computing resources and support, as well as the funding from Radboudumc and RIMLS Nijmegen (Hypatia tenure track fellowship), the “Deutsche Forschungsgemeinschaft” (DFG CRC1140 KIDGEM) and the European Research Council (ERC StG TREATCilia, grant No 716344). The biochemistry work was supported by the Association Franc¸aise contre les Myopathies (grant#21532; J.D.). S.W. is supported by the Ministry of Science, Research and the Arts of Baden-W{\"u}rttemberg and the European Social Fund (ESF) of Baden-W{\"u}rttemberg (31–7635 41/67/1). References: Anazi, S., Maddirevula, S., Faqeih, E., Alsedairy, H., Alzahrani, F., Shamseldin, H.E., Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield (2017) Mol Psychiatry, 22, pp. 615-624; Arancibia-Carcamo, I.L., Attwell, D., The node of Ranvier in CNS pathology (2014) Acta Neuropathol, 128, pp. 161-175; Bussi, G., Donadio, D., Parrinello, M., Canonical sampling through velocity rescaling (2007) J Chem Phys, 126, p. 014101; Buttermore, E.D., Piochon, C., Wallace, M.L., Philpot, B.D., Hansel, C., Bhat, M.A., Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development (2012) J Neurosci, 32, pp. 4724-4742; Carithers, L.J., Ardlie, K., Barcus, M., Branton, P.A., Britton, A., Buia, S.A., A novel approach to high-quality postmortem tissue procurement: The GTEx project (2015) Biopreserv Biobank, 13, pp. 311-319; Chemin, J., Siquier-Pernet, K., Nicouleau, M., Barcia, G., Ahmad, A., Medina-Cano, D., De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene (2018) Brain, 141, pp. 1998-2013; Cortese, A., Devaux, J.J., Zardini, E., Manso, C., Taieb, G., Carra Dalliere, C., Neurofascin-155 as a putative antigen in combined central and peripheral demyelination (2016) Neurol Neuroimmunol Neuroinflamm, 3; Delmont, E., Manso, C., Querol, L., Cortese, A., Berardinelli, A., Lozza, A., Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy (2017) Brain, 140, pp. 1851-1858; Devaux, J.J., Antibodies to gliomedin cause peripheral demyelinating neuropathy and the dismantling of the nodes of Ranvier (2012) Am J Pathol, 181, pp. 1402-1413; Devaux, J.J., New insights on the organization of the nodes of Ranvier (2014) Rev Neurol (Paris), 170, pp. 819-824; Devaux, J.J., Miura, Y., Fukami, Y., Inoue, T., Manso, C., Belghazi, M., Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy (2016) Neurology, 86, pp. 800-807; Fabregat, A., Korninger, F., Viteri, G., Sidiropoulos, K., Marin-Garcia, P., Ping, P., Reactome graph database: Efficient access to complex pathway data (2018) PLoS Comput Biol, 14; Farwell Hagman, K.D., Shinde, D.N., Mroske, C., Smith, E., Radtke, K., Shahmirzadi, L., Candidate-gene criteria for clinical reporting: Diagnostic exome sequencing identifies altered candidate genes among 8{\%} of patients with undiagnosed diseases (2017) Genet Med, 19, pp. 224-235; Ghosh, A., Sherman, D.L., Brophy, P.J., The axonal cytoskeleton and the assembly of nodes of ranvier (2018) Neuroscientist, 24, pp. 104-110; Hengel, H., Magee, A., Mahanjah, M., Vallat, J.M., Ouvrier, R., Abu-Rashid, M., CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis (2017) Neurol Genet, 3; Hess, B., P-LINCs: A parallel linear constraint solver for molecular simulation (2008) J Chem Theory Comput, 4, pp. 116-122; The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans (2015) Science, 348, pp. 648-660; Johnson, W.E., Li, C., Rabinovic, A., Adjusting batch effects in microarray expression data using empirical Bayes methods (2007) Biostatistics, 8, pp. 118-127; Kanehisa, M., Sato, Y., Kawashima, M., Furumichi, M., Tanabe, M., KEGG as a reference resource for gene and protein annotation (2016) Nucleic Acids Res, 44, pp. D457-D462; Kawamura, N., Yamasaki, R., Yonekawa, T., Matsushita, T., Kusunoki, S., Nagayama, S., Anti-neurofascin antibody in patients with combined central and peripheral demyelination (2013) Neurology, 81, pp. 714-722; Labasque, M., Hivert, B., Nogales-Gadea, G., Querol, L., Illa, I., Faivre-Sarrailh, C., Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies (2014) J Biol Chem, 289, pp. 7907-7918; Langfelder, P., Horvath, S., WGCNA: An R package for weighted correlation network analysis (2008) BMC Bioinform, 9, p. 559; Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects (2014) Hum Mol Genet, 23, pp. 2279-2289; Leek, J.T., Storey, J.D., Capturing heterogeneity in gene expression studies by surrogate variable analysis (2007) PLoS Genet, 3, pp. 1724-1735; Lindorff-Larsen, K., Piana, S., Palmo, K., Maragakis, P., Klepeis, J.L., Dror, R.O., Improved side-chain torsion potentials for the Amber ff99SB protein force field (2010) Proteins, 78, pp. 1950-1958; Maluenda, J., Manso, C., Quevarec, L., Vivanti, A., Marguet, F., Gonzales, M., Mutations in GLDN, encoding gliomedin, a critical component of the nodes of ranvier, are responsible for lethal arthrogryposis (2016) Am J Hum Genet, 99, pp. 928-933; McKenzie, I.A., Ohayon, D., Li, H., De Faria, J.P., Emery, B., Tohyama, K., Motor skill learning requires active central myelination (2014) Science, 346, pp. 318-322; Mencacci, N.E., Kamsteeg, E.J., Nakashima, K., R'Bibo, L., Lynch, D.S., Balint, B., De novo mutations in PDE10A cause childhood-onset chorea with bilateral striatal lesions (2016) Am J Hum Genet, 98, pp. 763-771; Monfrini, E., Straniero, L., Bonato, S., Monzio Compagnoni, G., Bordoni, A., Dilena, R., Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy (2019) Parkinsonism Relat Disord, 63, pp. 66-72; Ogata, H., Yamasaki, R., Hiwatashi, A., Oka, N., Kawamura, N., Matsuse, D., Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy (2015) Ann Clin Transl Neurol, 2, pp. 960-971; Pronk, S., Pall, S., Schulz, R., Larsson, P., Bjelkmar, P., Apostolov, R., GRomacS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit (2013) Bioinformatics, 29, pp. 845-854; Querol, L., Nogales-Gadea, G., Rojas-Garcia, R., Diaz-Manera, J., Pardo, J., Ortega-Moreno, A., Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg (2014) Neurology, 82, pp. 879-886; Querol, L., Siles, A.M., Alba-Rovira, R., Jauregui, A., Devaux, J., Faivre-Sarrailh, C., Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy (2017) Sci Rep, 7, p. 14411; Retterer, K., Juusola, J., Cho, M.T., Vitazka, P., Millan, F., Gibellini, F., Clinical application of whole-exome sequencing across clinical indications (2016) Genet Med, 18, pp. 696-704; Sherman, D.L., Tait, S., Melrose, S., Johnson, R., Zonta, B., Court, F.A., Neurofascins are required to establish axonal domains for saltatory conduction (2005) Neuron, 48, pp. 737-742; Smigiel, R., Sherman, D.L., Rydzanicz, M., Walczak, A., Mikolajkow, D., Krolak-Olejnik, B., Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia (2018) Hum Mol Genet, 27, pp. 3669-3674; Taylor, A.M., Shi, Q., Bhat, M.A., Simultaneous ablation of neuronal neurofascin and ankyrin g in young and adult mice reveals age-dependent increase in nodal stability in myelinated axons and differential effects on the lifespan (2018) eNeuro, 5. , ENEURO.0138-18.2018; Vallat, J.M., Mathis, S., Magy, L., Bounolleau, P., Skarzynski, M., Heitzmann, A., Subacute nodopathy with conduction blocks and anti-neurofascin 140/186 antibodies: An ultrastructural study (2018) Brain, 141; Xiao, L., Ohayon, D., McKenzie, I.A., Sinclair-Wilson, A., Wright, J.L., Fudge, A.D., Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning (2016) Nature Neurosci, 19, p. 1210; Zeisel, A., Hochgerner, H., Lonnerberg, P., Johnsson, A., Memic, F., Van Der Zwan, J., Molecular architecture of the mouse nervous system (2018) Cell, 174, pp. 999e22-1014e22; Zhang, Y., Sloan, S.A., Clarke, L.E., Caneda, C., Plaza, C.A., Blumenthal, P.D., Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse (2016) Neuron, 89, pp. 37-53",
year = "2019",
doi = "10.1093/brain/awz248",
language = "English",
volume = "142",
pages = "2948--2964",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

AU - SYNAPS Study Group

AU - Efthymiou, S.

AU - Salpietro, V.

AU - Malintan, N.

AU - Poncelet, M.

AU - Kriouile, Y.

AU - Fortuna, S.

AU - De Zorzi, R.

AU - Payne, K.

AU - Henderson, L.B.

AU - Cortese, A.

AU - Maddirevula, S.

AU - Alhashmi, N.

AU - Wiethoff, S.

AU - Ryten, M.

AU - Botia, J.A.

AU - Provitera, V.

AU - Schuelke, M.

AU - Vandrovcova, J.

AU - Walsh, L.

AU - Torti, E.

AU - Iodice, V.

AU - Najafi, M.

AU - Karimiani, E.G.

AU - Maroofian, R.

AU - Siquier-Pernet, K.

AU - Boddaert, N.

AU - De Lonlay, P.

AU - Cantagrel, V.

AU - Aguennouz, M.

AU - El Khorassani, M.

AU - Schmidts, M.

AU - Alkuraya, F.S.

AU - Edvardson, S.

AU - Nolano, M.

AU - Devaux, J.

AU - Houlden, H.

AU - Groppa, S.

AU - Karashova, B.M.

AU - Nachbauer, W.

AU - Boesch, S.

AU - Veggiotti, P.

AU - Ferrari, M.D.

AU - Marseglia, G.

AU - Savasta, S.

AU - Garavaglia, B.

AU - Borgione, E.

AU - Portaro, S.

AU - Scuderi, C.

AU - Minetti, C.

AU - Rinaldi, S.

N1 - Cited By :1 Export Date: 14 January 2020 CODEN: BRAIA Correspondence Address: Houlden, H.; Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, United Kingdom; email: h.houlden@ucl.ac.uk Funding details: Wellcome Trust, WT Funding details: Muscular Dystrophy UK, MDUK Funding details: Ataxia UK Funding details: European Social Fund, ESF Funding details: Deutsche Forschungsgemeinschaft, DFG, DFG CRC1140 KIDGEM Funding details: Medical Research Council, MRC, MR/S01165X/1, G0601943, MR/S005021/1 Funding details: Brain Research UK Funding details: National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology Funding details: Multiple System Atrophy Trust, MSAT Funding details: 716344 Funding details: Association Française contre les Myopathies, AFM, 21532 Funding details: European Research Council, ERC Funding details: Muscular Dystrophy Association, MDA Funding details: Media Development Authority - Singapore, MDA, HP10CRVL7F Funding details: Ministry of Science,Technology and Research, MoSTR Funding details: College of Environmental Science and Forestry, State University of New York, ESF, 7635 41/67/1 Funding details: Rosetrees Trust Funding text 1: We greatly appreciate the financial support provided by The Wellcome Trust and strategic award (Synaptopathies) Funding text 2: funding (WT093205 MA and WT104033AIA). Grunt funding was provided by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). We also acknowledge the CINECA Awards N. HP10CRVL7F, 2017, for the availability of high-performance computing resources and support, as well as the funding from Radboudumc and RIMLS Nijmegen (Hypatia tenure track fellowship), the “Deutsche Forschungsgemeinschaft” (DFG CRC1140 KIDGEM) and the European Research Council (ERC StG TREATCilia, grant No 716344). The biochemistry work was supported by the Association Franc¸aise contre les Myopathies (grant#21532; J.D.). S.W. is supported by the Ministry of Science, Research and the Arts of Baden-Württemberg and the European Social Fund (ESF) of Baden-Württemberg (31–7635 41/67/1). References: Anazi, S., Maddirevula, S., Faqeih, E., Alsedairy, H., Alzahrani, F., Shamseldin, H.E., Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield (2017) Mol Psychiatry, 22, pp. 615-624; Arancibia-Carcamo, I.L., Attwell, D., The node of Ranvier in CNS pathology (2014) Acta Neuropathol, 128, pp. 161-175; Bussi, G., Donadio, D., Parrinello, M., Canonical sampling through velocity rescaling (2007) J Chem Phys, 126, p. 014101; Buttermore, E.D., Piochon, C., Wallace, M.L., Philpot, B.D., Hansel, C., Bhat, M.A., Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development (2012) J Neurosci, 32, pp. 4724-4742; Carithers, L.J., Ardlie, K., Barcus, M., Branton, P.A., Britton, A., Buia, S.A., A novel approach to high-quality postmortem tissue procurement: The GTEx project (2015) Biopreserv Biobank, 13, pp. 311-319; Chemin, J., Siquier-Pernet, K., Nicouleau, M., Barcia, G., Ahmad, A., Medina-Cano, D., De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene (2018) Brain, 141, pp. 1998-2013; Cortese, A., Devaux, J.J., Zardini, E., Manso, C., Taieb, G., Carra Dalliere, C., Neurofascin-155 as a putative antigen in combined central and peripheral demyelination (2016) Neurol Neuroimmunol Neuroinflamm, 3; Delmont, E., Manso, C., Querol, L., Cortese, A., Berardinelli, A., Lozza, A., Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy (2017) Brain, 140, pp. 1851-1858; Devaux, J.J., Antibodies to gliomedin cause peripheral demyelinating neuropathy and the dismantling of the nodes of Ranvier (2012) Am J Pathol, 181, pp. 1402-1413; Devaux, J.J., New insights on the organization of the nodes of Ranvier (2014) Rev Neurol (Paris), 170, pp. 819-824; Devaux, J.J., Miura, Y., Fukami, Y., Inoue, T., Manso, C., Belghazi, M., Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy (2016) Neurology, 86, pp. 800-807; Fabregat, A., Korninger, F., Viteri, G., Sidiropoulos, K., Marin-Garcia, P., Ping, P., Reactome graph database: Efficient access to complex pathway data (2018) PLoS Comput Biol, 14; Farwell Hagman, K.D., Shinde, D.N., Mroske, C., Smith, E., Radtke, K., Shahmirzadi, L., Candidate-gene criteria for clinical reporting: Diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases (2017) Genet Med, 19, pp. 224-235; Ghosh, A., Sherman, D.L., Brophy, P.J., The axonal cytoskeleton and the assembly of nodes of ranvier (2018) Neuroscientist, 24, pp. 104-110; Hengel, H., Magee, A., Mahanjah, M., Vallat, J.M., Ouvrier, R., Abu-Rashid, M., CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis (2017) Neurol Genet, 3; Hess, B., P-LINCs: A parallel linear constraint solver for molecular simulation (2008) J Chem Theory Comput, 4, pp. 116-122; The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans (2015) Science, 348, pp. 648-660; Johnson, W.E., Li, C., Rabinovic, A., Adjusting batch effects in microarray expression data using empirical Bayes methods (2007) Biostatistics, 8, pp. 118-127; Kanehisa, M., Sato, Y., Kawashima, M., Furumichi, M., Tanabe, M., KEGG as a reference resource for gene and protein annotation (2016) Nucleic Acids Res, 44, pp. D457-D462; Kawamura, N., Yamasaki, R., Yonekawa, T., Matsushita, T., Kusunoki, S., Nagayama, S., Anti-neurofascin antibody in patients with combined central and peripheral demyelination (2013) Neurology, 81, pp. 714-722; Labasque, M., Hivert, B., Nogales-Gadea, G., Querol, L., Illa, I., Faivre-Sarrailh, C., Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies (2014) J Biol Chem, 289, pp. 7907-7918; Langfelder, P., Horvath, S., WGCNA: An R package for weighted correlation network analysis (2008) BMC Bioinform, 9, p. 559; Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects (2014) Hum Mol Genet, 23, pp. 2279-2289; Leek, J.T., Storey, J.D., Capturing heterogeneity in gene expression studies by surrogate variable analysis (2007) PLoS Genet, 3, pp. 1724-1735; 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PY - 2019

Y1 - 2019

N2 - 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. © 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

AB - 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. © 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

KW - Neurodevelopment

KW - Neurofascin

KW - Peripheral demyelination

KW - cell adhesion molecule

KW - isoprotein

KW - neurofascin

KW - neurofascin 155

KW - unclassified drug

KW - adolescent

KW - adult

KW - Article

KW - cell aggregation

KW - child

KW - clinical article

KW - controlled study

KW - demyelinating neuropathy

KW - demyelination

KW - developmental delay

KW - embryo

KW - female

KW - fibronectin type III domain

KW - frameshift mutation

KW - gene mutation

KW - human

KW - human cell

KW - human tissue

KW - immunofluorescence test

KW - immunohistochemistry

KW - intellectual impairment

KW - male

KW - mental disease

KW - motor dysfunction

KW - myelinated nerve

KW - preschool child

KW - priority journal

KW - protein expression

KW - school child

KW - speech disorder

KW - whole exome sequencing

KW - whole genome sequencing

KW - young adult

U2 - 10.1093/brain/awz248

DO - 10.1093/brain/awz248

M3 - Article

VL - 142

SP - 2948

EP - 2964

JO - Brain

JF - Brain

SN - 0006-8950

IS - 10

ER -