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Case Reports
. 2018 Nov 1;27(21):3669-3674.
doi: 10.1093/hmg/ddy277.

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

Robert Smigiel  1 , Diane L Sherman  2 , Malgorzata Rydzanicz  3 , Anna Walczak  3 , Dorota Mikolajkow  4 , Barbara Krolak-Olejnik  4 , Joanna Kosinska  3 , Piotr Gasperowicz  3 , Anna Biernacka  3 , Piotr Stawinski  3 , Malgorzata Marciniak  5 , Witalij Andrzejewski  6 , Maria Boczar  7 , Pawel Krajewski  8 , Maria M Sasiadek  9 , Peter J Brophy  2 , Rafal Ploski  3
Affiliations
Case Reports

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

Robert Smigiel et al. Hum Mol Genet. .

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.

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Figures

Figure 1
Figure 1
Results of genetic analyses of rs755160624 (NM_015090.3 c.2491C>T, (p.Arg831Ter) in the NFASC gene. (A) WES in proband (IGV view), (B–D) results of Sanger sequencing and ADS confirming the homozygosity of proband (B total count 11436, C-143 (1%), T-11207 (98%)), and demonstrating heterozygosity of her mother (C total count 9774, C-4823 (49%), T-4902 (50%)) and father (D total count 12620, C-6317 (50), T-6245 (49%)).
Figure 2
Figure 2
Schematic view of the domain structure of neuronal and glial human Neurofascin isoforms, Nfasc186 (NM_001005388.2) and Nfasc155 (NM_001160331.1), showing the exons that encode the five Fibronectin Type III (FNIII) repeats. The homozygous rs755160624 variant found in the proband creates a stop codon in the third FNIII repeat specific to the glial Nfasc155 isoform.
Figure 3
Figure 3
Nfasc155 is absent at the paranode of peripheral myelinated axons. Sections (5 mm thick) of biopsies from control and proband glabrous skin from infants of 11 and 2 months of age, respectively, were stained by immunofluorescence to reveal myelinated axons using antibodies against both MBP and NF-H. (A) The presence of both nodal neuronal NFASC isoforms (Nfasc186 and Nfasc140) at the node and glial Nfasc155 at the paranodal axoglial junction is revealed by staining with a pan-Nfasc antibody in the control. However, only the nodal isoforms are present in proband nerve fibres. The glial paranodal Nfasc155 is missing. (B) An antibody specific for glial Nfasc155 immunostains the paranodes of control but not proband nerve fibres, confirming the absence of this NFASC isoform in the proband. (C) Caspr is an axonal component of the paranodal axoglial complex with glial Nfasc155. Loss of Caspr at the paranodes in the proband confirms that the paranodal junction is disrupted due to the loss of Nfasc155. The arrowheads point to the location of paranodes and the arrows point to nodes. Size marker, 5 mm.
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