Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia

Abstract

The Neurofascins (NFASCs) are a family of proteins encoded by alternative transcripts of NFASC that cooperate in the assembly of the node of Ranvier in myelinated nerves. Differential expression of NFASC in neurons and glia presents a remarkable example of cell-type specific expression of protein isoforms with a common overall function. In mice there are three NFASC isoforms: Nfasc186 and Nfasc140, located in the axonal membrane at the node of Ranvier, and Nfasc155, a glial component of the paranodal axoglial junction. Nfasc186 and Nfasc155 are the major isoforms at mature nodes and paranodes, respectively. Conditional deletion of the glial isoform Nfasc155 in mice causes severe motor coordination defects and death at 16–17 days after birth. We describe a proband with severe congenital hypotonia, contractures of fingers and toes, and no reaction to touch or pain. Whole exome sequencing revealed a homozygous NFASC variant chr1:204953187-C>T (rs755160624). The variant creates a premature stop codon in 3 out of four NFASC human transcripts and is predicted to specifically eliminate Nfasc155 leaving neuronal Neurofascin intact. The selective absence of Nfasc155 and disruption of the paranodal junction was confirmed by an immunofluorescent study of skin biopsies from the patient versus control. We propose that the disease in our proband is the first reported example of genetic deficiency of glial Neurofascin isoforms in humans and that the severity of the condition reflects the importance of the Nfasc155 in forming paranodal axoglial junctions and in determining the structure and function of the node of Ranvier.

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

“…A homozygous NFASC variant rs755160624 predicted to cause the selective loss of the glial-specific Nfasc155 isoform was found in a child with a severe and progressive neurological disease. The variant, clinical phenotype, and related immunofluorescence study confirming the absence of the Nfasc155 isoform in the patient have been published separately as a description of a novel Mendelian disease [34]. Recently, our report has been confirmed by a description of a series of patients with the NFASC disorder [43].…”

“…The homozygous variant NM_015090.3:p.(Arg831*)/c.2491C>T in NFASC was described in detail in our previous paper [34].…”

Loss of Neurofascin-186 Disrupts Alignment of AnkyrinG Relative to Its Binding Partners in the Axon Initial Segment

“…While in null mice the glial NF-155 is also ablated (Sherman et al, 2005), these isoforms remain in our cultures. However, the selective knockout of NF-155 produces independent impairments (Smigiel et al, 2018), arguing against potentially redundant transcellular signaling by NF-155 within the extracellular matrix (ECM). Furthermore, NF-140 has remained understudied until recently.…”

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene

“…Despite the declared non‐consanguinity of proband's parents, the analysis of runs of homozygosity (ROH) performed as previously described showed evidence for their relatedness. The total ROH length was 57.76 Mb.…”

“…The MTCL1 gene is constrained for predicted biallelic loss of function mutations in the general population according to the ExAC data (pRec = 0.9941). 9 Despite the declared non-consanguinity of proband's parents, the analysis of runs of homozygosity (ROH) performed as previously described 10 showed evidence for their relatedness. The total ROH length was 57.76 Mb.…”