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

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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

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