Objective: We aim to find the genetic defect causing infantile-onset ataxia and mild demyelinating neuropathy in two siblings of an Italian consanguineous family.

Background: Neurofascin is a neuronal transmembrane protein with an essential role in nervous system development and Ranvier’s node function.

Method: Family members were genotyped with array-SNP and linkage analysis was performed. Whole-exome sequencing (WES) was performed on one sibling. Moreover, we produced induced pluripotent stem cells (iPSCs) starting from patients’ fibroblasts that were then differentiated to neurons. Functional studies were performed to evaluate neurofascin expression by immunofluorescence and western blot analysis.

Results: A homozygous missense mutation (p.V1122E) in the NFASC gene, coding for neurofascin, was identified in the affected siblings combining linkage analysis and WES. The identified mutation affects a highly conserved hydrophobic transmembrane residue; we confirmed in iPSCs-derived neurons of affected siblings that this variant leads to significant loss of Neurofascin protein.

Conclusion: The identification of NFASC as a causative gene for a neurological disorder opens the way for genetic research in the developing field of nodopathies, an emerging pathological entity involving Ranvier’s nodes, never associated with a genetic disorder so far.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurofascin-is-a-novel-gene-associated-with-autosomal-recessive-spastic-and-polyneuropathy/