Neurofascin 140 is an embryonic neuronal neurofascin isoform that promotes the assembly of the node of Ranvier.

Rapid nerve conduction in myelinated nerves requires the clustering of voltage-gated sodium channels at nodes of Ranvier. The Neurofascin (Nfasc) gene has a unique role in node formation because it encodes glial and neuronal isoforms of neurofascin (Nfasc155 and Nfasc186, respectively) with key functions in assembling the nodal macromolecular complex. A third neurofascin, Nfasc140, has also been described; however, neither the cellular origin nor function of this isoform was known. Here we show that Nfasc140 is a neuronal protein strongly expressed during mouse embryonic development. Expression of Nfasc140 persists but declines during the initial stages of node formation, in contrast to Nfasc155 and Nfasc186, which increase. Nevertheless, Nfasc140, like Nfasc186, can cluster voltage-gated sodium channels (Nav) at the developing node of Ranvier and can restore electrophysiological function independently of Nfasc155 and Nfasc186. This suggests that Nfasc140 complements the function of Nfasc155 and Nfasc186 in initial stages of the assembly and stabilization of the nodal complex. Further, Nfasc140 is reexpressed in demyelinated white matter lesions of postmortem brain tissue from human subjects with multiple sclerosis. This expands the critical role of the Nfasc gene in the function of myelinated axons and reveals further redundancy in the mechanisms required for the formation of this crucial structure in the vertebrate nervous system.

Zhang A ，Desmazieres A ，Zonta B ，Melrose S ，Campbell G ，Mahad D ，Li Q ，Sherman DL ，Reynolds R ，Brophy PJ ... -  《-》

Differential stability of PNS and CNS nodal complexes when neuronal neurofascin is lost.

Desmazieres A ，Zonta B ，Zhang A ，Wu LM ，Sherman DL ，Brophy PJ ... -  《-》

Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system.

Zonta B ，Tait S ，Melrose S ，Anderson H ，Harroch S ，Higginson J ，Sherman DL ，Brophy PJ ... -  《-》

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

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.

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 ... -  《-》

Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis.

Howell OW ，Palser A ，Polito A ，Melrose S ，Zonta B ，Scheiermann C ，Vora AJ ，Brophy PJ ，Reynolds R ... -  《-》